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Pharmaceuticals

Pharmaceuticals -> Antibiotics

Pharmaceuticals -> Listed in ZINC15

Crystals

White to pale yellow crystalline powder

SOL IN ACETONE, CHLOROFORM, ETHYL ACETATE; SLIGHTLY SOL IN WATER, BENZENE, TOLUENE

Freely soluble in alcohol; soluble in polyethylene glycol 400

Slightly soluble in ether

3.7 [ug/mL] (The mean of the results at pH 7.4)

Breast Feeding; Lactation; Milk, Human; Antifungal Agents; Dermatologic Agents

FDA approved drugs -> Active ingredient

FDA approved drugs -> Active ingredient

Antifungal medicines

Active Ingredients (Clotrimazole) -> FDA Greenbook

Pharmaceuticals -> UK Veterinary Medicines Directorate List

147-149 °C

148 °C

This chemical does not meet GHS hazard criteria for 1.5% (3 of 196) of reports.

Danger

H302 (96.9%): Harmful if swallowed [Warning Acute toxicity, oral]

P203, P260, P262, P264, P264+P265, P270, P273, P280, P301+P317, P302+P352, P305+P351+P338, P316, P318, P319, P321, P330, P332+P317, P337+P317, P361+P364, P362+P364, P391, P405, and P501 (click each P-code to see the statement)

Aggregated GHS information provided per 196 reports by companies from 15 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

Hazard Traits - Bioaccumulation; Environmental Persistence

Clotrimazole: Does not have an individual approval but may be used under an appropriate group standard

Clotrimazole cream. (a) Specifications: Each g of cream contains 10 mg of clotrimazole ... (c) Conditions of use: Apply 1/4 in ribbon of cream per sq in of lesion for 2 to 4 wk ... For the treatment of fungal infections of dogs and cats caused by Microsporum canis and Trichophyton mentagrophytes ... Wash hands thoroughly after use to avoid spread of infection. Federal law restricts this drug to use by or on the order of a licensed veterinarian.

A synergistic effect of clotrimazole and certain anionic surfactants against a strain of Candida albicans was confirmed. Measurement of apparent partition coefficients indicated that lipophilic ion pairs between clotrimazole and anionic surfactants were formed. It is suggested that the synergistic effect of the drugs may be due to ion pair formation.

Transient elevations in serum aminotransferase levels occur in up to 15% of patients treated with clotrimazole orally. The elevations are generally mild-to-moderate in degree and resolve spontaneously with or without discontinuation. Despite decades of widespread use, clotrimazole has not been linked to instances of clinically apparent hepatotoxicity.

The adverse effects of the oral formulation include itching, nausea, and vomiting. More than 10% of patients receiving oral clotrimazole (troche) may have abnormal liver function tests. For this reason, patients receiving oral clotrimazole (troche) should have their liver function tests periodically monitored.

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

Clotrimazole interacts with yeast 14-α demethylase, a cytochrome P-450 enzyme that converts lanosterol to ergosterol, an essential component of the membrane. In this way, clotrimazole inhibits ergosterol synthesis, resulting in increased cellular permeability. Clotrimazole may also inhibit endogenous respiration, interact with membrane phospholipids, inhibit the transformation of yeasts to mycelial forms and the uptake of purine, impair triglyceride and/or phospholipid biosynthesis, and inhibit the movement of calcium and potassium ions across the cell membrane by blocking the ion transport pathway known as the Gardos channel.

In a small fraction of recipients, clotrimazole on the skin may cause stinging, erythema, edema, vesication, desquamation, pruritus, and urticaria. Applied to the vagina, about 1.6% of recipients complain of a mild burning sensation and, rarely, of lower abdominal cramps, slight increase in urinary frequency, or skin rash. Occasionally, the sexual partner may experience penile or urethral irritation. By the oral route, clotrimazole can cause mild gastrointestinal irritation. In patients using troches, the incidence is about 5%.

No adverse effects have been reported to date in humans when clotrimazole was administered intravaginally in the second or third trimesters of pregnancy; however, intravaginal use of the drug during the first trimester of pregnancy has not been studied. Since clotrimazole is absorbed in small amounts from the vagina, the drug should not be used intravaginally in the first trimester of pregnancy unless the drug is considered essential to the welfare of the patient.

Adverse effects after topical use of clotrimazole include erythema; stinging, blistering, and peeling of the skin; edema; pruritus; and urticaria. Adverse reactions after use of the troche form include nausea and vomiting (incidence, about 5%). Reversible elevation of SGOT to abnormal levels has occurred in 15% of patients receiving troches. The manufacturer recommends periodic assessment of hepatic function, particularly in patients with pre-existing hepatic impairment. The safety and effectiveness of clotrimazole troches in children less than 3 years has not been established; therefore, use of this dosage form in these patients is not recommended.

Seventy three patients with rheumatoid arthritis were randomized in a double blind study to receive either clotrimazole (20 mg/kg/day) 2 days/wk for 12 wk or matching placebo. Patients receiving clotrimazole had significant improvements (p< 0.05) from baseline in measurements of grip strength, joint count, and patient assessment of pain, but did not show significant improvement over patients treated with placebo. More adverse experiences, predominantly gastrointestinal complaints, occurred in patients taking clotrimazole resulting in 9 patients discontinuing therapy.

For more Human Toxicity Excerpts (Complete) data for CLOTRIMAZOLE (6 total), please visit the HSDB record page.

Drug Induced Liver Injury Rank (DILIrank 2.0)

Clotrimazole

vLess-DILI-concern

3

Warnings & precautions

DOI:10.1016/j.drudis.2016.02.015

SHOWED MODERATE TOXICITY AFTER ORAL ADMIN. SOLN OR CREAM WERE WELL TOLERATED BY SKIN OF RABBIT & CONJUNCTIVA.

Clotrimazole inhibits or kills many fungi, including yeast and dermatophytes. The drug is also active against some gram positive bacteria. In vitro, clotrimazole concentrations of 1 ug/ml or less inhibit most strains of Trichlophyton rubrum, T. mentagrophytes, Epidermophyton floccosum, and Microsporum canis. At a concentration of 3 ug/ml or less, clotrimazole inhibits most other susceptible organisms including Malassezia furfur (Pityrosporum orbiculare), Aspergillus fumigatus, Candida albicans, some strains of Staphylococcus aureaus and Streptococcus pyogenes, and a few strains of Proteus vulgaris and Salmonella in vitro. Clotrimazole is also active in vitro against Sporothrix, Cryptococcus, Cephalosporium, and Fusarium. Clotrimazole concentrations of 100 ug/ml are required to inhibit Trichomonas vaginalis.

Clotrimazole has been shown to be embryotoxic in rats and mice when given in oral doses 100 times the usual human dose; this effect may be secondary to maternal toxicity. Clotrimazole has not been teratogenic in mice, rabbits, or rats when given in oral doses up to 200, 180, or 100 times the human dose, respectively. In addition, reproduction studies in mice using oral clotrimazole, at a dosage 120 times the usual human dose and administered from 9 weeks prior to mating through weaning, resulted in impairment of mating, decreased number of viable young, and decreased survival to weaning; no effects were observed when doses 60 times the usual human dose were used. In similar studies in rats using oral doses 50 times the usual human dose, there was a slight decrease in the number of pups per litter and decreased pup viability.

Clotrimazole is embryotoxic in rats and mice when given in doses 100 times the adult human dose (in mg/kg), possibly secondary to maternal toxicity. The drug was not teratogenic in mice, rabbits, and rats when given in doses up to 200 times the human dose.

◉ Summary of Use during Lactation

◈ What is clotrimazole?

LD50 Rat, male oral 708 mg/kg

LD50 Mouse, male oral 923 mg/kg

Clotrimazole cream. (a) Specifications: Each g of cream contains 10 mg of clotrimazole ... (c) Conditions of use: Apply 1/4 in ribbon of cream per sq in of lesion for 2 to 4 wk ... For the treatment of fungal infections of dogs and cats caused by Microsporum canis and Trichophyton mentagrophytes ... Wash hands thoroughly after use to avoid spread of infection. Federal law restricts this drug to use by or on the order of a licensed veterinarian.

G01AF02

A - Alimentary tract and metabolism

G - Genito urinary system and sex hormones

D - Dermatologicals

QA - Alimentary tract and metabolism

QG - Genito urinary system and sex hormones

Clotrimazole is a broad-spectrum antifungal agent that inhibits the growth of pathogenic yeasts by changing the permeability of cell membranes. The action of clotrimazole is fungistatic at concentrations of drug up to 20 mcg/mL and may be fungicidal _in vitro_ against Candida albicans and other species of the genus Candida at higher concentrations. Unfortunately, resistance to clotrimazole, which was rare in the past, is now common in various patient populations. Clotrimazole is generally considered to be a fungistatic, and not a fungicidal drug, although this contrast is not absolute, as clotrimazole shows fungicidal properties at higher concentrations.

Clotrimazole acts primarily by damaging the permeability barrier in the cell membrane of fungi. Clotrimazole causes inhibition of ergosterol biosynthesis, an essential constituent of fungal cell membranes. If ergosterol synthesis is either completely or partially inhibited, the cell is no longer able to construct an intact and functional cell membrane,. Because ergosterol directly promotes the growth of fungal cells in a hormone‐like fashion, rapid onset of the above events leads to dose-dependent inhibition of fungal growth. Though decreased ergosterol, due to the inhibition of lanosterol 14-demethylase (also known as _CYP51_) is accepted to be primarily responsible for the antimycotic properties of clotrimazole, this drug also shows other pharmacological effects. 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. The action of clotrimazole on these targets accounts for other effects of this drug that are separate from its antimycotic activities.

Clotrimazole exerts its antifungal activity by altering cell membrane permeability, apparently by binding with phospholipids in the fungal cell membrane. In contrast to polyene antibiotics (eg, amphotericin B), the action of clotrimazole is less dependent on the sterol content of the cell membrane. As a result of alteration of permeability, the cell membrane is unable to function as a selective barrier, and potassium and other cellular constituents are lost.

Clotrimazole was given by mouth in a dose of 1.5 g to 7 healthy subjects and 47 patients and peak blood concentrations of up to 1 ug/ml were detected microbiologically at 2 or 4 hours. The half-life was between 3.5 and 5.5 hours.

Clotrimazole was absorbed from the gastrointestinal tract and had a biological half-life of about 4 hours. Liver and kidney dysfunction had little influence on serum concentrations or half-life.

Hepatic (metabolized to inactive metabolites).

Clotrimazole ... is metabolized in the liver to inactive compounds ... .

The effect of the antifungal imidazole compound, clotrimazole, on the metabolism of benzo[a]pyrene was studied in cultured keratinocytes prepared from BALB/c mouse epidermis. Varying concentrations of clotrimazole added to the cultured keratinocytes resulted in a dose dependent inhibition of the activities of the microsomal cytochrome p450 dependent monooxygenases aryl hydrocarbon hydroxylase and 7-ethoxycoumarin O-deethylase. The major organic solvent soluble metabolites of benzo(a)pyrene identified in the cultured cells were trans-7,8-dihydro-7,8-dihydroxybenzo(a)pyrene, 9-hydroxybenzo(a)pyrene, and 3-hydroxybenzo(a)pyrene, although small amounts of trans-4,5-dihydro-4,5-dihydroxybenzo(a)pyrene, benzo(a)pyrene-quinones, and trans-9,10-dihydroxybenzo(a)pyrene were also present. The major organic solvent extractable metabolites of benzo(a)pyrene found in the extracellular culture medium were primarily the diols with smaller quantities of phenols and quinones. The major water soluble metabolites of benzo(a)pyrene present both intracellularly and extracellularly were glucuronide conjugates of 3-hydroxybenzo(a)pyrene, 9-hydroxybenzo(a)pyrene, and benzo(a)pyrene-3,6-dione and to a lesser extent sulfate conjugates (primarily of the trans-7,8-dihydro-7,8- dihydroxybenzo(a)pyrene). Clotrimazole inhibited the generation of organic solvent soluble and water soluble conjugates in a dose dependent manner. The in vitro metabolism of benzo(a)pyrene by microsomes prepared from control and benz(a)anthracene induced cultured keratinocytes was also inhibited by clotrimazole with greater inhibitory effect on benz(a)anthracene induced keratinocytes especially with respect to the formation of diols and quinones. The enzyme mediated covalent binding of benzo(a)pyrene to mouse keratinocyte DNA and protein was also substantially diminished by clotrimazole in a dose dependent fashion. These results indicate that clotrimazole, a widely used drug for the management of a variety of superficial dermatophyte infections of the skin, is a potent inhibitor of cytochrome p450 dependent transformation of polycyclic aromatic hydrocarbons in cultured murine keratinocytes. This system offers a convenient approach for studies as inhibitors of carcinogen metabolism in the epidermis.

Hepatic (metabolized to inactive metabolites) Half Life: 2 hours

G07GZ97H65

CLOTRIMAZOLE

Established Pharmacologic Class [EPC] - Azole Antifungal

Chemical Structure [CS] - Azoles

Clotrimazole is an Azole Antifungal.

CLOTRIMAZOLE

Substances used on humans and other animals that destroy harmful microorganisms or inhibit their activity. They are distinguished from DISINFECTANTS, which are used on inanimate objects.

Substances that destroy fungi by suppressing their ability to grow or reproduce. They differ from FUNGICIDES, INDUSTRIAL because they defend against fungi present in human or animal tissues.

Compounds that specifically inhibit STEROL 14-DEMETHYLASE. A variety of azole-derived ANTIFUNGAL AGENTS act through this mechanism.

Because clotrimazole is generally not significantly absorbed, drug interactions are not a major issue with its use.

Mainly hepatic.

The topical form is minimally absorbed in the serum and tissues. Clotrimazole is a lipophilic drug, and has been shown to be secreted in breastmilk in animal studies. There are limited data available regarding the volume of distribution following oral troche administration.

GIVEN ORALLY OR IV WAS ABSORBED, DISTRIBUTED, ELIMINATED READILY. EXCRETED AS INACTIVE METABOLITE IN BILE, LITTLE IN URINE.

Absorption of clotrimazol is less than 0.5% after application to the intact skin: from the vagina, it is 3 to 10%. Fungicidal concentrations remain in the vagina for as long as 3 days after application of the drug. The small amount absorbed is metabolized in the liver and excreted in bile. In adults, an oral dose of 200 mg per day will give rise to plasma concentrations of 0.2 to 0.35 ug/ml.

Only very small amounts of clotrimazole appear to be absorbed systemically following topical application to the skin. Following application to the skin, highest concentrations of clotrimazole are present in the stratum corneum; lower drug concentrations occur in the stratum spinosum and the papillary and reticular dermis. Small amounts of clotrimazole are absorbed systemically when the drug is administered intravaginally. Following intravaginal administration of radiolabeled clotrimazole in patients with normal or inflamed vaginal mucosa, peak serum concentrations of clotrimazole 24 hours after insertion of a single 100 mg tablet of the drug are 0.03 ug/ml and peak serum concentrations 24 hours after administration of a cream containing 50 mg of the drug are 0.01 ug/ml. About 3-10% of an intravaginal dose of the drug reaches systemic circulation, principally as metabolites.

MEDICATION

MEDICATION (VET)

Use (kg) in Switzerland (2009): >100

For the local treatment of oropharyngeal candidiasis and vaginal yeast infections, also used in fungal infections of the skin such as ringworm, athlete's foot, and jock itch.

Topical: Lotrimin (Schering), Mycelex (Miles). Cream 1% in 15, 30, 45 (Lotrimin only), and 90 g containers; solution 1% in 10 and 30 ml containers; and lotion 1% (Lotrimin only) in 30 ml containers; intravaginal: Gyne-Lotrimin (Schering) Cream (vaginal) 1% in 45 g containers; tablets (vaginal) 100 and 500 mg; Mycelex-G (Miles) cream (vaginal) 1% in 45 and 90 g containers; tablets 100 and 500 mg; and 500 mg with cream 1% in 7 g containers. Oral: troche 10 mg.

Mycelex 1% cream

Animal Drugs -> FDA Approved Animal Drug Products (Green Book) -> Active Ingredients

Cosmetics -> Antimicrobial; Antidandruff