Clotrimazole

344.83700

344.84

245-764-8

G07GZ97H65

756700|257473

DTXSID7029871

C381

Crystals|White to pale yellow crystalline powder

G01AF02|A - Alimentary tract and metabolism|D - Dermatologicals|G - Genito urinary system and sex hormones

2933290012

17.82000

5.37670

Solid

1.13g/cm3

147-149 °C

482.3ºC at 760mmHg

245.5ºC

1.616

<10mg/L(25 ºC)

Store at RT.

5.42E-09mmHg at 25°C

LD50 in male mice, rats (mg/kg): 923, 708 orally (Tettenborn)

Odorless

WEAK BASE

4.1None

4.1

NONH for all modes of transport

3

R22

S26; S36

NI4377000

Xn

P301 + P312 + P330

H302

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.

|Danger|H302 (99.09%): Harmful if swallowed [Warning Acute toxicity, oral]|P201, P202, P260, P264, P270, P273, P280, P281, P301+P312, P302+P352, P305+P351+P338, P308+P313, P312, P314, P321, P322, P330, P332+P313, P337+P313, P361, P362, P363, P391, P405, and P501|Aggregated GHS information provided by 333 companies from 14 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

Adverse effects after topical use of clotrimazole include stinging.

Symptoms of overdose include erythema, stinging, blistering, peeling, edema, pruritus, urticaria, burning, and general irritation of the skin, and cramps. As with all topical agents, skin sensitization may result. **Oral LD50 (rat)**: 708 mg/kg; **Intraperitoneal LD50 (rat)**: 445 mg/kg; **Subcutaneous LDLO (rat)**: 10 g/kg; **Oral LD50 (mouse)**: 761 mg/kg; **Subcutaneous LDLO (mouse)**: 10 g/kg; **Intraperitoneal LD50 (mouse)**: 108 mg/kg; **Overdose** This drug poses no risk of acute intoxication, as it is unlikely to occur following a single vaginal or dermal application of an overdose (application over a large area under conditions favorable to absorption) or accidental oral ingestion. There is no specific antidote. **Effects on Fertility** No human studies of the effects of clotrimazole on fertility have been conducted; however, animal studies have not shown any effects on the drug on fertility. **Use in Pregnancy** There are limited data regarding the use of clotrimazole in pregnant women. Animal studies do not show direct or indirect harmful effects on reproduction. Although the topical application of clotrimazole may result in very low serum and tissue levels, the use of clotrimazole topical cream by pregnant women is not recommended unless it is advised by the prescribing physician. Clotrimazole topical cream should not be used in the first trimester of pregnancy unless it is considered by the physician to be essential to patient well-being. **Use in Breastfeeding** Available pharmacodynamic/toxicological studies in animals have shown excretion of clotrimazole/metabolites in breastmilk. Clotrimazole should not be administered during breastfeeding. Although the topical application of clotrimazole has resulted in very low serum and tissue levels, the use of clotrimazole topical cream by lactating women is not recommended unless it recommended by the prescribing physician.

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.

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.

LD50 Rat, male oral 708 mg/kg|LD50 Mouse, male oral 923 mg/kg

98%

**Topical preparations** Clotrimazole topical cream is indicated for the topical treatment of the following dermal infections,: Tinea pedis, tinea cruris, and tinea corporis due to _Trichophyton rubrum_, _Trichophyton mentagrophytes_, _Epidermophyton floccosum_ Candidiasis due to _Candida albicans_ Tinea versicolor due to _Malassezia furfur_ Diaper rash infected by _Candida albicans_ In some preparations, clotrimazole may be combined with betamethasone dipropionate, a corticosteroid. **Oral preparations** The oral troche preparation is indicated for the local treatment of oropharyngeal candidiasis. It is also indicated as a prophylactic drug to reduce the incidence of oropharyngeal candidiasis in patients immunocompromised by conditions such as chemotherapy, radiotherapy, or steroid therapy utilized in the treatment of leukemia, solid tumors, or renal transplantation. Troche preparations are not indicated for the treatment of any systemic mycoses.|FDA Label

Clotrimazole is an imidazole antifungal agent used primarily in the treatment of skin, oral and vaginal candida infections. Clotrimazole is typically given topically or as oral or vaginal troches and has only modest systemic absorption. Nevertheless, clotrimazole given orally or as troches has been associated with transient and asymptomatic serum aminotransferase elevations during therapy, but it has not been linked to instances of clinically apparent acute liver injury.

Antifungal Agents

Anti-Infective Agents, Local; Antifungal Agents; Growth Inhibitors|CLOTRIMAZOLE IS A CHLORINATED IMIDAZOLE DERIVATIVE THAT IS USED TO TREAT TOPICAL FUNGAL, DERMATOPHYTE, & YEAST INFECTIONS. WHILE CLOTRIMAZOLE HAS MARKED IN VITRO ACTIVITY AGAINST MANY FUNGI, IT IS OF LITTLE VALUE IN TREATMENT OF SYSTEMIC MYCOSES.|VAGINAL: 1 TABLET (100 MG) IS INSERTED DAILY FOR 1 WK FOR CANDIDAL VAGINITIS. TOPICAL: SUFFICIENT CREAM OR SOLN IS APPLIED TWICE DAILY TO SKIN INFECTED WITH CANDIDA ALBICANS, TRICOPHYTON, OR MICROSPORUM SPECIES. 2 WK OF THERAPY IS USUALLY SUFFICIENT.|CLOTRIMAZOLE HAS BEEN USED INVESTIGATIONALLY FOR ORAL TREATMENT OF MUCOCUTANEOUS CANDIDIASIS.|For more Therapeutic Uses (Complete) data for CLOTRIMAZOLE (12 total), please visit the HSDB record page.

PREPN OF CLOTRIMAZOLE ARE NOT INTENDED FOR OPHTHALMIC USE & SHOULD BE USED WITH CAUTION AROUND EYES.|Clotrimazole lozenges should not be used for the treatment of systemic myotic infections.|Clotrimazole Vaginal tablets ... single-dose therapy is not recommended for the treatment of severe vulvovaginal candidiasis.|To achieve maximum theraputic effect of clotrimazole when the drug is administered orally as a lozenge, the lozenge must be dissolved slowly in the mouth. Therefore, patients receiving clotrimazole lozenges must be of such age and physical and/or mental condition that they can comprehend and follow administration instruction. Liver function tests should be conducted periodically during oral therapy with clotrimazole lozenges, especially in patients with preexisting hepatic impairment.|Clotrimazole topical cream, lotion, and solution should be used during the first trimester of pregnancy only when the drug is considered essential to the welfare of the patient. Since it is not known whether clotrimazole is distributed into milk, the drug should be used with caution in nursing women.

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.

Compounds that specifically inhibit STEROL 14-DEMETHYLASE. A variety of azole-derived ANTIFUNGAL AGENTS act through this mechanism. (See all compounds classified as 14-alpha Demethylase Inhibitors.)|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. (See all compounds classified as Anti-Infective Agents, Local.)|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. (See all compounds classified as Antifungal Agents.)

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.|Clotrimazole is absorbed from the gastrointestinal tract ... and excreted in the feces and urine. When applied topically clotrimazole penetrates the epidermis but there is little if any systemic absorption. Slight absorption has been reported following the administration of vaginal tablets.

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.

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.

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.

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.

Bay b 5097

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

A systemic preparation is not available in the United States.

Clotrimazole responds to the thin layer chromatographic identification test. A solution containing about 20 mg/ml of clotrimazole in chloroform is used as the test solution, and a solvent system consisting of a mixture of xylene, n-propyl alcohol, and ammonium hydroxide are used.|Clotrimazole in ointments was dissolved in trichloromethane and determined by 3-wavelength spectrophotometry at lambda1 = 255.9 nm, lambda2 = 267.0 nm, and lambda3 = 280.0 nm; the linear calibration curve was at 0.1-0.5 mg/ml. The average recovery was 99.77%.|Derivative spectrophotometric determination of clotrimazole in single formulations and in combination with other drugs eg, creams, topical solutions, and vaginal tablets, relative standard deviation is < 2%.|Determination of clotrimazole by second order derivative UV spectrophotometry.|For more Analytic Laboratory Methods (Complete) data for CLOTRIMAZOLE (8 total), please visit the HSDB record page.

Post chromatographic derivatization in quantitative high performance thin layer chromatography for the determination of drugs and metabolites in human biological fluids.

Human Drugs -> FDA Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book) -> Active Ingredients|Animal Drugs -> FDA Approved Animal Drug Products (Green Book) -> Active Ingredients|Cosmetics -> Antidandruff; Antimicrobial