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IMIDAZOLE ANTIFUNGALS

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) This class of drugs includes broad-spectrum imidazole antifungal agents that interfere with ergosterol synthesis, altering the permeability of the cell membrane of susceptible fungi. Imidazole antifungal agents are "azole" antimycotic agents.

Specific Substances

    A) BIFONAZOLE (SYNONYM)
    1) 1-(alpha-Biphenyl-4-ylbenzyl)imidazole
    2) Bay-h-4502
    3) Bifonazolum
    4) Molecular Formula: C22-H18-N2
    5) CAS 60628-96-8
    BUTOCONAZOLE (SYNONYM)
    1) 1-[4-(4-Chlorophenyl)-2-
    2) (2,6-dichlorophenylthio)butyl]-
    3) imidazole mononitrate
    4) RS-35887
    5) RS-35887-00-10-3
    6) Molecular Formula: C19-H17-Cl3-N2-S,HNO(3)
    7) CAS 64872-76-0 (butoconazole)
    8) CAS 64872-77-1 (butoconazole nitrate)
    CLOTRIMAZOLE (SYNONYM)
    1) 1-(alpha-2-Chlorotrityl)imidazole
    2) Bay-5097
    3) Clotrimazolum
    4) FB-5097
    5) Molecular Formula: C22-H17-Cl-N2
    6) CAS 23593-75-1
    CROCONAZOLE (SYNONYM)
    1) 1-(1-{o-[(m- -Chlorobenzyl)oxy]phenyl}vinyl)- imidazole hydrochloride
    2) Cloconazole Hydrochloride
    3) 710674-S (croconazole)
    4) Croconazol
    5) Croconazolum
    6) Molecular Formula: C18-H15-Cl-N2-O,HCl
    7) CAS 77175-51-0 (croconazole)
    ECONAZOLE NITRATE (SYNONYM)
    1) (+/-)-1-[2,4-Dichloro-beta-(4-chlorobenzyloxy) phenethyl]imidazole nitrate
    2) 1-(2-((4-Chlorophenyl)methoxy)-2-(2,4-dichlorophenyl) ethyl)-1H-imidazole mononitrate
    3) C-C2470
    4) Econazoli Nitras
    5) R-14827
    6) SQ-13050
    7) Molecular Formula: C18-H15-Cl3-N2-O,HNO(3)
    8) CAS 27220-47-9 (econazole)
    9) CAS 24169-02-6 (econazole nitrate)
    EFINACONAZOLE (SYNONYM)
    1) CAS 164650-44-6
    FENTICONAZOLE (SYNONYM)
    1) (+/-)-1-[2,4-Dichloro-beta-{[p- -(phenylthio)
    2) benzyl]oxy}- phenethyl]imidazole mononitrate
    3) Fenticonazole nitrate
    4) Fenticonazoli Nitras
    5) Fenticonazolo
    6) Fenticonazolum
    7) REC-15/1476
    8) Molecular Formula: C24-H20-Cl2-N2-O-S,HNO(3)
    9) CAS 73151-29-8 (fenticonazole nitrate)
    10) CAS 72479-26-6 (fenticonazole)
    OMOCONAZOLE (SYNONYM)
    1) (Z)-1-{2,4-Dichloro-beta-[2-(p- chlorophenoxy)ethoxy]-alpha-methylstyryl}imidazole nitrate
    2) Omoconazole nitrate
    3) 10-80-07
    4) Molecular Formula: C20-H-17-Cl3-N2-O2, -HNO(3)
    5) CAS 74512-12-2 (omoconazole)
    6) CAS 83621-06-1 (omoconazole nitrate)
    OXICONAZOLE (SYNONYM)
    1) 2',4'-Dichloro-2-imidazol-1-ylacetophenone(Z)-O- -(2,4-dichlorobenzyl)oxime mononitrate
    2) Oxiconazole nitrate
    3) Ro-13-8996
    4) Molecular Formula: C18-H13-Cl4-N3-O,HNO(3)
    5) CAS 64211-46-7 (oxiconazole nitrate)
    6) CAS 64211-45-6 (oxiconazole)
    SERTACONAZOLE (SYNONYM)
    1) (+/-)-1-{2,4-Dichloro-beta-[(7- -chlorobenzo[b]thien-3- -yl) methoxy]phenethyl}imidazole nitrate
    2) Sertaconazole nitrate
    3) FI-7045
    4) Sertaconazoli Nitras
    5) Molecular Formula: C20-H15-Cl3-N2-O-S,HNO(3)
    6) CAS 99592-32-2 (sertaconazole)
    7) CAS 99592-39-9 (sertaconazole nitrate)
    SULCONAZOLE (SYNONYM)
    1) 1-[2,4-Dichloro-beta-(4- -chlorobenzyl) thiophenethyl]imidazole nitrate
    2) Sulconazole nitrate
    3) RS-44872
    4) Molecular Formula: C18-H15-Cl-3-N2-S,HNO(3)
    5) CAS 61318-90-9 (sulconazole)
    6) CAS 61318-91-0 (sulconazole nitrate)
    TIOCONAZOLE (SYNONYM)
    1) 1-[2,4-Dichloro-beta-(2-chloro-3- -thenyloxy) phenethyl]imidazole
    2) UK-20349
    3) Molecular Formula: C16-H13-Cl3-N2-O-S
    4) CAS 65899-73-2

    1.2.1) MOLECULAR FORMULA
    1) BIFONAZOLE: C22H18N2
    2) CLOTRIMAZOLE: C22H17ClN2
    3) CROCONAZOLE HYDROCHLORIDE: C18H15ClN2O.HCl
    4) ECONAZOLE NITRATE: C18H15Cl3N2O.HNO3
    5) EFINACONAZOLE: C18H22F2N4O
    6) FENTICONAZOLE NITRATE: C24H20Cl2N2OS.HNO3
    7) LULICONAZOLE: C14H9CI2N3S2
    8) OMOCONAZOLE NITRATE: C20H17Cl3N2O2.HNO3
    9) OXICONAZOLE NITRATE: C18H13ON3CI4.HNO3
    10) SERTACONAZOLE NITRATE: C20H15Cl3N2OS.HNO3
    11) TIOCONAZOLE: C16H13Cl3N2OS

Available Forms Sources

    A) FORMS
    1) The following antifungals are available in a variety of formulations (eg, cream, lozenges, ointment, vaginal suppository) in the United States: Butaconazole, clotrimazole, econazole, efinaconazole, oxiconazole, sertaconazole, sulconazole, and tioconazole (Prod Info ERTACZO(R) topical cream, 2014; Goldust et al, 2013; Prod Info JUBLIA(R) 10% topical solution, 2014; Prod Info GYNAZOLE-1(R) vaginal cream, 2006; Prod Info clotrimazole troche oral lozenges, 2005; Prod Info ECONAZOLE NITRATE topical cream, 2013; Prod Info ECOZA topical foam, 2013; Prod Info OXISTAT(R) cream, lotion, 2004; Prod Info EXELDERM(R) topical cream, 2003; Prod Info EXELDERM(R) topical solution, 2003; Prod Info MONISTAT(R) vaginal ointment, 2001).
    B) USES
    1) Imidazole antifungals (ie, butaconazole, clotrimazole, econazole, efinaconazole, oxiconazole, sertaconazole, sulconazole, and tioconazole) are broad-spectrum agents that interfere with ergosterol synthesis, altering the permeability of the cell membrane of susceptible fungi. Imidazole antifungal agents are "azole" antimycotic agents (Prod Info ERTACZO(R) topical cream, 2014; Goldust et al, 2013; Prod Info JUBLIA(R) 10% topical solution, 2014; Prod Info GYNAZOLE-1(R) vaginal cream, 2006; Prod Info clotrimazole troche oral lozenges, 2005; Prod Info ECONAZOLE NITRATE topical cream, 2013; Prod Info ECOZA topical foam, 2013; Prod Info OXISTAT(R) cream, lotion, 2004; Prod Info EXELDERM(R) topical cream, 2003; Prod Info EXELDERM(R) topical solution, 2003; Prod Info MONISTAT(R) vaginal ointment, 2001).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Imidazole agents (ie, butaconazole, clotrimazole, econazole, efinaconazole, oxiconazole, sertaconazole, sulconazole, and tioconazole) are broad-spectrum "azole" antifungals.
    B) PHARMACOLOGY: These drugs are fungistatic and may be fungicidal, depending on concentration. Imidazoles inhibit biosynthesis of ergosterol or other sterols, damaging the fungal cell membrane and altering its permeability. As a result, loss of essential intracellular elements may occur.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) Allergic contact dermatitis to these agents is rare but has been reported. Following dermal applications, pruritus, erythema, stinging, urticaria and localized edema have been reported. Nausea, vomiting, and diarrhea are frequent side effects following oral administration of clotrimazole. Elevated liver enzymes have rarely been reported following the use of clotrimazole troches and sertaconazole 2% topical cream. Drowsiness and disorientation have been reported following oral clotrimazole therapy. Headache may infrequently occur following therapeutic use of these agents.
    E) WITH POISONING/EXPOSURE
    1) Overdose experience is limited with these agents. Due to minimal oral absorption and limited systemic toxicity, severe toxic effects following oral overdose is not anticipated. Ingestion of even large quantities should produce only minor GI symptoms (eg, nausea, vomiting, and diarrhea).
    0.2.20) REPRODUCTIVE
    A) Butoconazole, clotrimazole troches, econazole, efinaconazole, luliconazole, sertaconazole sulconazole, and tioconazole are in pregnancy category C; clotrimazole topical/vaginal and oxiconazole are in pregnancy category B.
    0.2.21) CARCINOGENICITY
    A) At the time of this review, the manufacturer does not report any human carcinogenic potential for efinaconazole, luliconazole, or sertaconazole.

Laboratory Monitoring

    A) No specific laboratory tests are necessary unless otherwise clinically indicated.
    B) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    C) Monitor serum electrolytes in patients with significant vomiting and/or diarrhea.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Treatment is symptomatic and supportive. Toxicity due to these agents is negligible.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Treatment is symptomatic and supportive. Significant toxicity is not expected after an overdose. Correct any significant fluid and/or electrolyte abnormalities in patients with severe diarrhea and/or vomiting. In patients with acute allergic reaction, oxygen therapy, bronchodilators, diphenhydramine, corticosteroids, vasopressors and epinephrine may be required.
    C) DECONTAMINATION
    1) Toxicity due to these agents is negligible. Even when large amounts have been ingested, ensuing symptoms are expected to be minor. GI decontamination is generally NOT indicated.
    D) AIRWAY MANAGEMENT
    1) Should not be required in these cases. Endotracheal intubation and mechanical ventilation may be required in patients with severe allergic reaction.
    E) ANTIDOTE
    1) None.
    F) ENHANCED ELIMINATION
    1) It is unknown if hemodialysis would be effective in overdose; however, hemodialysis is not recommended given the low toxicity of these drugs.
    G) PATIENT DISPOSITION
    1) HOME CRITERIA: A patient with an inadvertent exposure, that remains asymptomatic can be managed at home.
    2) OBSERVATION CRITERIA: Patients with a deliberate overdose, and those who are symptomatic, need to be monitored until they are clearly improving and clinically stable.
    3) ADMISSION CRITERIA: Patients with severe symptoms despite treatment should be admitted. If significant toxicity develops, other causes should be sought.
    4) CONSULT CRITERIA: Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.
    H) PITFALLS
    1) If significant toxicity develops, other causes should be sought. When managing a suspected overdose, the possibility of multidrug involvement should be considered.
    I) DIFFERENTIAL DIAGNOSIS
    1) Includes other agents that cause nausea, vomiting, or diarrhea.

Range Of Toxicity

    A) TOXICITY: A minimum toxic dose has not been established, and significant toxicity is not expected after an overdose. Ingestion of even large quantities should produce only minor GI symptoms (eg, nausea, vomiting, and diarrhea). THERAPEUTIC DOSE: Varies by agent. Topical application is mainly once or twice a day for 7 to 14 days.

Clinical Effects

Summary Of Exposure

    A) USES: Imidazole agents (ie, butaconazole, clotrimazole, econazole, efinaconazole, oxiconazole, sertaconazole, sulconazole, and tioconazole) are broad-spectrum "azole" antifungals.
    B) PHARMACOLOGY: These drugs are fungistatic and may be fungicidal, depending on concentration. Imidazoles inhibit biosynthesis of ergosterol or other sterols, damaging the fungal cell membrane and altering its permeability. As a result, loss of essential intracellular elements may occur.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) Allergic contact dermatitis to these agents is rare but has been reported. Following dermal applications, pruritus, erythema, stinging, urticaria and localized edema have been reported. Nausea, vomiting, and diarrhea are frequent side effects following oral administration of clotrimazole. Elevated liver enzymes have rarely been reported following the use of clotrimazole troches and sertaconazole 2% topical cream. Drowsiness and disorientation have been reported following oral clotrimazole therapy. Headache may infrequently occur following therapeutic use of these agents.
    E) WITH POISONING/EXPOSURE
    1) Overdose experience is limited with these agents. Due to minimal oral absorption and limited systemic toxicity, severe toxic effects following oral overdose is not anticipated. Ingestion of even large quantities should produce only minor GI symptoms (eg, nausea, vomiting, and diarrhea).

Heent

    3.4.3) EYES
    A) ANIMALS: The corneal epithelial toxicity of 1% clotrimazole in three vehicles (powdered clotrimazole in castor oil and ethylene dioxide (Cremophor(R)), Mycelex(R) solution, and Mycelex(R) cream) was tested in rabbits (Gilbert et al, 1987). The Mycelex(R) cream produced only trace to mild conjunctival erythema. The Mycelex(R) solution caused significant irritation and produced marked conjunctival erythema and mild to moderate periorbital swelling. The Cremophor(R) vehicles caused mild to moderate conjunctival erythema.
    3.4.6) THROAT
    A) Unpleasant mouth sensations have been reported following the use of clotrimazole troches (Product Information , 2000b).

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) ELECTROCARDIOGRAM ABNORMAL
    1) WITH THERAPEUTIC USE
    a) Abnormal electrocardiogram findings were reported in an 8-year-old boy who received 70 mg/kg/day or oral clotrimazole over a period of 45 days for a pulmonary aspergilloma. ECG findings revealed electrical alternans and inverted T waves which may have been drug-induced. Clotrimazole was discontinued but the abnormal ECG abnormalities persisted for a period of 5 weeks. No other signs or symptoms of toxicity were noted in this patient. The authors concluded that the ECG abnormalities were probably NOT related to clotrimazole (Evans et al, 1971).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) DROWSY
    1) Depression, drowsiness, disorientation, and visual alterations have occurred following oral clotrimazole therapy (Sawyer et al, 1975). Neurological reactions (drowsiness, confusion, depression) occurred in 26% of patients treated in 1 study resulting in discontinuation of medication in a few patients (Holt, 1974).
    B) HEADACHE
    1) Headache was reported in 5% of patients in two clinical trials involving 1060 study subjects looking at vaginal tioconazole use (Prod Info Vagistat(R), 1994).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) NAUSEA, VOMITING AND DIARRHEA
    1) CLOTRIMAZOLE: Nausea, vomiting, and diarrhea are frequent side effects following oral administration of clotrimazole and have resulted in reduction of dosage or discontinuation of therapy (Product Information , 2000b; Wahlberg, 1974; Cartwright, 1974).
    a) One investigator reported severe nausea, vomiting, and diarrhea in all of 5 patients treated with clotrimazole for rheumatoid arthritis. Three of these patients experienced significant weight loss (3 to 3.5 kg) and antiemetics were required to control persistent vomiting (Lund-Olesen, 1977).
    b) Anorexia, nausea, vomiting, and alopecia were reported in patients receiving 3.5 g/day of oral clotrimazole for Candida albicans septicemia (Malchow et al, 1972). These symptoms subsided when the dosage was reduced.
    B) ABDOMINAL PAIN
    1) WITH THERAPEUTIC USE
    a) BUTOCONAZOLE: Abdominal pain was reported in patients who received butoconazole nitrate vaginal cream in controlled clinical trials (n=314) (Prod Info GYNAZOLE-1(R) vaginal cream, 2006).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) LIVER ENZYMES ABNORMAL
    1) Following therapy with clotrimazole troches, abnormal liver function tests have been reported; approximately 15% of patients in clinical trials were reported to have elevated SGOT levels (Product Information , 2000b).
    a) Hepatic abnormalities were reported in 10% to 15% of 145 patients receiving oral clotrimazole for pulmonary mycosis in doses of 20 mg/kg 3 times a day (Weuta, 1974). Elevations in AST, ALT, and bilirubin levels were noted.
    b) One report noted that transient increases in AST and ALT following 3 months of therapy with oral clotrimazole occurred in a 43-year-old female with pleural aspergillosis (Huguenin-Dumittan, 1972).
    2) There have been isolated instances of serum aminotransferase elevations reported after multiple-dose administration of sertaconazole 2% topical cream. These elevated levels normalized after discontinuation of treatment (Farre et al, 1992).

Genitourinary

    3.10.2) CLINICAL EFFECTS
    A) DYSURIA
    1) Patients treated with imidazole antifungal vaginal products have reported (rarely): dysuria, slight urinary frequency, lower abdominal cramping, and dyspareunia (Product Information , 2000b; Prod Info Vagistat(R), 1994). These effects, however, are difficult to differentiate from those of the underlying disorder being treated.
    B) VAGINITIS
    1) Following intravaginal administration of the imidazoles, the most common side effects include: vaginal burning or stinging, vulvar itching, vaginal discharge, as well as, vaginal soreness and swelling (Wiest & Ruffmann, 1987; Bradbeer et al, 1985; Jacobson et al, 1985). An objectionable odor has been reported in up to 20% of patients using butoconazole (Bradbeer et al, 1985). These effects are difficult to differentiate from those of the underlying disorder being treated.
    a) In an unblinded study, a localized burning sensation developed in 3 of 60 patients following the use of fenticonazole vaginal 200 mg or 100 mg ovules (Wiest & Ruffmann, 1987).

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) THROMBOCYTOPENIC DISORDER
    1) BUTOCONAZOLE was associated with thrombocytopenia following vaginal administration for a yeast infection in a 54-year-old woman. The patient had a 19-year history of rheumatoid arthritis and was receiving methotrexate 7.5 mg/week, ibuprofen 800 mg 4 times daily, sucralfate 1 gram 4 times daily, and an antacid. One week after starting butoconazole, the patient developed epigastric pain and a positive stool Hematest for occult blood. A complete blood count revealed a white blood cell count of 2.4x10(9)/L, hemoglobin of 62 g/L, and platelet count of 8x10(9)/L. The patient recovered after discontinuation of all medications and blood product administration. Methotrexate (10 mg/week) and ibuprofen (800 mg 4 times daily) were re-instituted without incident. The positive stool Hematest was thought to be due to gastric bleeding caused by methotrexate, ibuprofen and butoconazole-induced thrombocytopenia. The possibility of a drug interaction with this combination of medications was not ruled out (Maloley et al, 1990).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) ITCHING OF SKIN
    1) WITH THERAPEUTIC USE
    a) Pruritus has been reported in some patients following the use of oral clotrimazole troches (Product Information , 2000b).
    b) Erythema, stinging, burning, pruritus, urticaria, and edema have been reported, although not common, in patients following the topical application of the imidazole antifungals (Product Information , 2000b; Product Information , 2000; Prod Info Oxistat(R), oxiconazole, 2000; Fachinformation, 1996; Alomar et al, 1992; Leiste et al, 1989; Benfield & Clissold, 1988; Sartani et al, 1988; Tanenbaum et al, 1984; Spiekermann & Young, 1976; Wahlberg, 1974). These effects are difficult to differentiate from those of the underlying disorder being treated.
    B) CONTACT DERMATITIS
    1) WITH THERAPEUTIC USE
    a) Cases of contact dermatitis associated with these drugs have been reported in the literature, but are not common (Cooper & Shaw, 1999; Steinmann et al, 1996; Shono et al, 1989; Raulin & Frosch, 1989; Raulin & Frosch, 1987; Kalb & Grossman, 1985).
    1) Local symptoms such as burning, itching, erythema, or irritation have been reported with topical formulations, although their incidence is relatively low (about 4% with bifonazole) (Galimberti et al, 1985; Belli et al, 1985a; del Palacio Hernanz et al, 1987; Hernandez-Perez, 1986; Lackner & Clissold, 1989).
    2) Comparative studies suggest that the nature and incidence of dermatological adverse effects is similar among all the topical imidazoles (Lackner & Clissold, 1989). Cross-sensitivity among the imidazoles should be considered in patients presenting with contact allergy to one imidazole (Baes, 1991).
    3) Nine patients with documented contact allergies to the imidazole antimycotics were tested for positive reactions to various imidazoles. The number of positive reactions, in decreasing order, were as follows: miconazole (6), clotrimazole (3), econazole (3), isoconazole (3), and oxiconazole (1). In this series, no cross-sensitivity was observed with bifonazole (Raulin & Frosch, 1989).
    b) CASE REPORT: A 71-year-old woman experienced severe exacerbation of her vulval dermatitis after a 6-week course of Canesten(R) cream, a topical preparation containing clotrimazole 1%. Patch testing confirmed clotrimazole to be the agent responsible for her reaction (Cooper & Shaw, 1999).
    c) CASE REPORT: A well-documented case of contact dermatitis to clotrimazole has been reported in a 60-year-old man. Two weeks after initiating topical clotrimazole therapy, the patient developed weeping vesicular lesions in the areas of drug application; the allergic reaction resolved after a course of systemic corticosteroids. Subsequent patch testing revealed allergy to clotrimazole only (not other ingredients in the product). Interestingly, the patient was not allergic to miconazole or econazole (Kalb & Grossman, 1985).
    d) CASE REPORT: Allergic contact dermatitis due to croconazole without cross-sensitivity to clotrimazole and bifonazole has been reported (Steinmann et al, 1996), but this is unusual.

Immunologic

    3.19.2) CLINICAL EFFECTS
    A) ALLERGIC CONTACT DERMATITIS
    1) Six cases of allergic contact dermatitis from croconazole cream or gel have been reported. All six reacted positively in patch testing to both croconazole cream and gel, but negatively to the base components. Four patients also reacted positively to tioconazole or sulconazole (Shono et al, 1989).
    2) Cross-sensitivity confirmed by patch testing has occurred with sulconazole and may be possible with other imidazoles. Within 3.5 years after its introduction, 14 cases of contact sensitivity had been reported in Japan (Baes, 1991; Lassus et al, 1983).
    3) Investigators found that the allergic cross-reaction between phenethyl imidazoles and phenmethyl imidazoles appears to be due to the common molecular structure 2-(2,4-dichlorophenyl)-ethyl imidazole (Faria et al, 1996).

Reproductive

    3.20.1) SUMMARY
    A) Butoconazole, clotrimazole troches, econazole, efinaconazole, luliconazole, sertaconazole sulconazole, and tioconazole are in pregnancy category C; clotrimazole topical/vaginal and oxiconazole are in pregnancy category B.
    3.20.2) TERATOGENICITY
    A) LACK OF INFORMATION
    1) SERTACONAZOLE
    a) At the time of this review, no data were available to assess the teratogenic potential of this agent (Prod Info ERTACZO(R) topical cream, 2014).
    B) LACK OF EFFECT
    1) CLOTRIMAZOLE
    a) Clotrimazole 100 mg vaginal tablets have been used safely in patients in their second and third trimesters of pregnancy, but have not been evaluated in patients during their first trimester (Prod Info MYCELEX(R)-G vaginal tablets, 1995; Haram & Digranes, 1978; Svendsen et al, 1978; Frerich & Gad, 1977; Tan et al, 1974).
    b) A study of clotrimazole use in pregnancy did not find an association between congenital abnormalities and use of clotrimazole (either vaginal pessaries or topical cream) during pregnancy. The study was based on the Hungarian Congenital Abnormality Registry. For newborns with congenital abnormalities (1307), two matched case controls were selected among newborns with no abnormalities (2539). Of the group with abnormalities at birth, 7.1% of the mothers used clotrimazole; 7.7% of mothers of babies in the control group used clotrimazole. The authors found that use of clotrimazole during pregnancy was associated with a lower prevalence of undescended testis (Czeizel et al, 1999).
    2) BUTOCONAZOLE
    a) A 2.9% incidence of birth defects in 1167 first-trimester exposures to butoconazole has been reported; however, no adverse effects to the mother or fetus have been associated with second- or third-trimester use of butoconazole (King et al, 1998).
    b) Administration of butoconazole nitrate 2% cream for 3 to 6 days in clinical studies involving over 200 pregnant patients (during the second- or third-trimester) produced no adverse effects on the course of pregnancy, and no fetal abnormalities were observed (Prod Info Femstat(R), butoconazole, 2000).
    3) CROCONAZOLE
    a) Placental transfer has been demonstrated in rats with croconazole; however, animal studies have not demonstrated any teratogenic effects. Oral doses from 50 mg/kg resulted in embryotoxicity and negative effects on gestation time and parturition in rats and rabbits. Topical croconazole is minimally absorbed, but should be used cautiously during pregnancy (Fachinfo Pilzcin(R), 1993).
    4) ECONAZOLE
    a) No congenital abnormality was observed in 107 infants born to women who were treated with econazole 150 mg vaginal suppositories for 3 days during 1 or 2 treatment courses (Goormans et al, 1985). Nearly 50% of the mothers were in the last month of pregnancy at the time of treatment.
    5) FENTICONAZOLE
    a) Oral fenticonazole has not demonstrated teratogenic potential in rats and rabbits. Embryotoxic effects occurred with doses of 80 mg/kg/day and higher (Fachinformation, 1992).
    6) OMOCONAZOLE
    a) High doses of omoconazole in animal studies have not produced teratogenic effects. Data regarding use in humans during pregnancy and lactation are lacking (Fachinformation, 1996).
    7) TIOCONAZOLE
    a) Administration of tioconazole vaginal ovules or cream during pregnancy in 38 women produced no adverse effects on the course of pregnancy, and no fetal abnormalities were observed (Adetoro, 1987).
    C) ANIMAL STUDIES
    1) ECONAZOLE
    a) In animal studies, there was no evidence of teratogenicity with oral econazole administration in mice, rabbits, or rats. However, embryotoxic effects were observed in rats administered oral doses that were 10 to 40 times the human dermal doses, and similar effects were noted in mice, rabbits, and/or rats administered oral doses that were 40 or 80 times the human dermal dose (Prod Info ECOZA topical foam, 2013; Prod Info ECONAZOLE NITRATE topical cream, 2013).
    2) EFINACONAZOLE
    a) In animal studies, subQ administration of efinaconazole was embryotoxic (increased embryofetal deaths, decreased number of live fetuses, and placental effects) at a maternally toxic dose of 50 mg/kg/day (559 times the maximum recommended human dose [MRHD] based on AUC) given to rats during organogenesis (gestation days 6 to 16). No malformations were noted at this dose. Subcutaneous efinaconazole was also embryotoxic (increased prenatal and postnatal pup mortality and reduced live litter sizes) at a maternally toxic dose of 25 mg/kg/day (89 times the MRHD based on AUC) given to rats from the beginning of organogenesis through the end of lactation (gestation day 6 to lactation day 20), although no effects on postnatal development were observed at this dose. Subcutaneous administration to rabbits was not embryotoxic or teratogenic at maternally toxic doses up to 10 mg/kg/day (154 times the MRHD based on AUC) given during organogenesis (gestation days 6 to 19) (Prod Info JUBLIA(R) 10% topical solution, 2014).
    3) LULICONAZOLE
    a) In animal studies, there was no evidence of major malformations with luliconazole subQ doses up to 25 mg/kg/day (approximately 3 times the maximum recommended human dose [MRHD] of 8 g/day of 1% cream based on body surface area [BSA]) administered to rats during organogenesis (gestation days 7 to 17); however, increased incidences of skeletal variation (fourteenth rib) were observed at the highest dose (25 mg/kg/day). This dose when administered from gestation day 7 through lactation day 20 to rats resulted in maternal toxicity and embryofetal toxicity (increased prenatal pup mortality, reduced live litter sizes, and increased postnatal pup mortality). No maternal toxicity, embryofetal toxicity, or malformations were observed with subQ doses up to 100 mg/kg/day (24 times the MRHD based on BSA) administered to rabbits during organogenesis (gestation days 6 to 18) (Prod Info LUZU topical cream, 2013)
    4) SERTACONAZOLE
    a) Embryotoxicity and teratogenicity were not observed in rats or rabbits at oral doses of 160 mg/kg/day (40 times and 80 times the maximum recommended human dose, based on body surface area, in rats and rabbits respectively) (Prod Info ERTACZO(R) topical cream, 2014).
    3.20.3) EFFECTS IN PREGNANCY
    A) LACK OF INFORMATION
    1) SERTACONAZOLE
    a) At the time of this review, no data were available to assess the potential effects of exposure to this agent during pregnancy in humans (Prod Info ERTACZO(R) topical cream, 2014).
    B) PREGNANCY CATEGORY
    1) Butoconazole, clotrimazole troches, econazole, efinaconazole, luliconazole, sertaconazole, sulconazole, and tioconazole have been classified as pregnancy category C (Prod Info JUBLIA(R) 10% topical solution, 2014; Prod Info LUZU topical cream, 2013; Prod Info ECOZA topical foam, 2013; Prod Info ECONAZOLE NITRATE topical cream, 2013; Prod Info GYNAZOLE-1(R) vaginal cream, 2006; Prod Info clotrimazole troche oral lozenges, 2005; Prod Info EXELDERM(R) topical cream, 2003; Prod Info EXELDERM(R) topical solution, 2003; Prod Info Vagistat(R), 1994; Prod Info ERTACZO(R) topical cream, 2014).
    2) Clotrimazole topical/vaginal and oxiconazole have been classified as pregnancy category B (Prod Info OXISTAT(R) cream, lotion, 2004; Prod Info TRIVAGIZOLE 3(TM) vaginal cream, 2000; Prod Info MYCELEX(R)-G vaginal tablets, 1995).
    C) EFINACONAZOLE
    1) There are no adequate and well-controlled studies of efinaconazole in pregnant women. It is recommended that efinaconazole be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus (Prod Info JUBLIA(R) 10% topical solution, 2014).
    D) LACK OF EFFECT
    1) ECONAZOLE
    a) Econazole given during pregnancy had no effect on the duration of pregnancy, duration and evaluation of delivery, or the outcome of delivery in an open multicenter study of 117 pregnant women with vaginal candidiasis (Goormans et al, 1985).
    E) ANIMAL STUDIES
    1) SERTACONAZOLE
    a) Embryotoxicity was not observed in rats or rabbits at oral doses of 160 mg/kg/day (40 times and 80 times the maximum recommended human dose, based on body surface area, in rats and rabbits respectively). A reduction in live birth indices and an increased number of stillborn pups were observed in rats administered oral sertaconazole at doses of 80 and 160 mg/kg/day during peri- and post-natal development (Prod Info ERTACZO(R) topical cream, 2014).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) LACK OF INFORMATION
    1) EFINACONAZOLE
    a) At the time of this review, no data were available to assess the potential effects of exposure to this agent during lactation in humans (Prod Info JUBLIA(R) 10% topical solution, 2014).
    2) SERTACONAZOLE
    a) At the time of this review, no data were available to assess the potential effects of exposure to this agent during lactation in human (Prod Info ERTACZO(R) topical cream, 2014).
    B) ANIMAL STUDIES
    1) ECONAZOLE
    a) In studies in lactating rats, econazole and/or metabolites were excreted in milk and detected in pups after oral administration of econazole nitrate (Prod Info ECOZA topical foam, 2013). Postpartum viability of pups and survival to weaning decreased when lactating rats received large oral doses (40 or 80 times the human dermal dose). Maternal toxicity also occurred at these high doses and could have contributed to the results (Prod Info ECONAZOLE NITRATE topical cream, 2013).
    2) EFINACONAZOLE
    a) Subcutaneous efinaconazole is excreted in the milk of lactating rats (Prod Info JUBLIA(R) 10% topical solution, 2014).
    3.20.5) FERTILITY
    A) LACK OF INFORMATION
    1) EFINACONAZOLE
    a) At the time of this review, no data were available to assess the potential effects on fertility from exposure to this agent in humans (Prod Info JUBLIA(R) 10% topical solution, 2014).
    2) SERTACONAZOLE
    a) At the time of this review, no data were available to assess the potential effects on fertility from exposure to this agent in humans (Prod Info ERTACZO(R) topical cream, 2014).
    B) LACK OF EFFECT
    1) ECONAZOLE
    a) intravaginal administration of econazole nitrate in humans has not been shown to cause prolonged gestation or other adverse reproductive effects (Prod Info ECONAZOLE NITRATE topical cream, 2013).
    C) ANIMAL STUDIES
    1) ECONAZOLE
    a) Studies in rats have shown that econazole given orally causes prolonged gestation (Prod Info ECOZA topical foam, 2013; Prod Info ECONAZOLE NITRATE topical cream, 2013).
    2) EFINACONAZOLE
    a) Studies in rats showed that subQ administration of doses up to 25 mg/kg/day (279 times the maximum recommended human dose based on AUC) prior to and during early pregnancy had no effects on fertility. However, doses of 25 mg/kg/day delayed the estrous cycle in female rats (Prod Info JUBLIA(R) 10% topical solution, 2014).
    3) LULICONAZOLE
    a) Subcutaneous administration prior to and during mating and through early pregnancy resulted in effects on reproductive function in female rats (decreased live embryos and decreased corpus luteum) at doses of 5 and 25 mg/kg/day and male rats (decreased sperm count) at 25 mg/kg/day (Prod Info LUZU topical cream, 2013).
    4) SERTACONAZOLE
    a) No reproductive or fertility effects were observed in male or female rats administered up to 60 mg/kg/day (16 times the maximum recommended human dose, based on body surface area) (Prod Info ERTACZO(R) topical cream, 2014).

Carcinogenicity

    3.21.2) SUMMARY/HUMAN
    A) At the time of this review, the manufacturer does not report any human carcinogenic potential for efinaconazole, luliconazole, or sertaconazole.
    3.21.4) ANIMAL STUDIES
    A) EFINACONAZOLE
    1) Daily topical administration of efinaconazole solution 3%, 10%, and 30% in mice resulted in severe irritation with all treatment groups during a 2-year dermal carcinogenicity study. This is likely attributable to the vehicle and confounded interpretation of skin effects. No drug-related neoplasms were reported at doses up to 10% (approximately 248 times the maximum recommended human dose) (Prod Info JUBLIA(R) 10% topical solution, 2014).
    B) LACK OF EFFECT
    1) SERTACONAZOLE
    a) Topical administration of sertaconazole nitrate cream in doses up to 800 mg/kg/day (200 times the maximum recommended human dose) for up to 102 weeks in rats did not increase the number of neoplastic lesions compared with controls (Prod Info ERTACZO(R) topical cream, 2014).

Genotoxicity

    A) EFINACONAZOLE
    1) There was no evidence of genotoxicity or mutagenicity in the following tests: the Ames assay, Chinese hamster lung cell chromosome aberration assay, and in vivo mouse peripheral reticulocyte micronucleus assay (Prod Info JUBLIA(R) 10% topical solution, 2014).
    B) FENTICONAZOLE
    1) Fenticonazole does not exhibit mutagenic activity, based on in-vitro tests (Fachinformation, 1992; Veronese et al, 1981). In the Ames assay, fenticonazole demonstrated a lack of mutagenicity (Veronese et al, 1981a).
    C) LULICONAZOLE
    1) There was no evidence of genotoxicity or mutagenicity in the following tests: the in vitro Ames assay, the in vitro Chinese hamster lung cell chromosomal aberration assay, and the in vivo mouse bone marrow micronucleus test (Prod Info LUZU topical cream, 2013).
    D) SERTACONAZOLE
    1) There was no evidence of genotoxicity or mutagenicity in the following tests: the mouse micronucleus test, the in vivo mouse sister chromatid exchange assay, and the unscheduled DNA synthesis assay in primary rat hepatocyte cultures (Prod Info ERTACZO(R) topical cream, 2014).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) No specific laboratory tests are necessary unless otherwise clinically indicated.
    B) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    C) Monitor serum electrolytes in patients with significant vomiting and/or diarrhea.

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.1) ADMISSION CRITERIA/ORAL
    A) Patients with severe symptoms despite treatment should be admitted. If significant toxicity develops, other causes should be sought.
    6.3.1.2) HOME CRITERIA/ORAL
    A) A patient with an inadvertent exposure, that remains asymptomatic can be managed at home.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) Patients with a deliberate overdose, and those who are symptomatic, need to be monitored until they are clearly improving and clinically stable.

Monitoring

    A) No specific laboratory tests are necessary unless otherwise clinically indicated.
    B) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    C) Monitor serum electrolytes in patients with significant vomiting and/or diarrhea.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) Toxicity due to these agents is negligible. Even when large amounts have been ingested, ensuing symptoms are expected to be minor. GI decontamination is generally NOT indicated.
    6.5.2) PREVENTION OF ABSORPTION
    A) Toxicity due to these agents is negligible. Even when large amounts have been ingested, ensuing symptoms are expected to be minor. GI decontamination is generally NOT indicated.
    6.5.3) TREATMENT
    A) SUPPORT
    1) MANAGEMENT OF MILD TO MODERATE TOXICITY
    a) Treatment is symptomatic and supportive. Toxicity due to these agents is negligible.
    2) MANAGEMENT OF SEVERE TOXICITY
    a) Treatment is symptomatic and supportive. Significant toxicity is not expected after an overdose. Correct any significant fluid and/or electrolyte abnormalities in patients with severe diarrhea and/or vomiting. In patients with acute allergic reaction, oxygen therapy, bronchodilators, diphenhydramine, corticosteroids, vasopressors and epinephrine may be required.
    B) MONITORING OF PATIENT
    1) No specific laboratory tests are necessary unless otherwise clinically indicated.
    2) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    3) Monitor serum electrolytes in patients with significant vomiting and/or diarrhea.
    C) ACUTE ALLERGIC REACTION
    1) SUMMARY
    a) Mild to moderate allergic reactions may be treated with antihistamines with or without inhaled beta adrenergic agonists, corticosteroids or epinephrine. Treatment of severe anaphylaxis also includes oxygen supplementation, aggressive airway management, epinephrine, ECG monitoring, and IV fluids.
    2) BRONCHOSPASM
    a) ALBUTEROL
    1) ADULT: 2.5 to 5 milligrams in 2 to 4.5 milliliters of normal saline delivered per nebulizer every 20 minutes up to 3 doses. If incomplete response administer 2.5 to 10 mg every 1 to 4 hours as needed, or 10 to 15 mg/hr by continuous nebulization as needed (National Heart,Lung,and Blood Institute, 2007). CHILD: 0.15 milligram/kilogram (minimum 2.5 milligrams) per nebulizer every 20 minutes up to 3 doses. If incomplete response administer 0.15 to 0.3 mg/kg (up to 10 mg) every 1 to 4 hours as needed, or 0.5 mg/kg/hr by continuous nebulization (National Heart,Lung,and Blood Institute, 2007).
    3) CORTICOSTEROIDS
    a) Consider systemic corticosteroids in patients with significant bronchospasm.
    b) PREDNISONE: ADULT: 40 to 80 milligrams/day. CHILD: 1 to 2 milligrams/kilogram/day (maximum 60 mg) in 1 to 2 divided doses divided twice daily (National Heart,Lung,and Blood Institute, 2007).
    4) MILD CASES
    a) DIPHENHYDRAMINE
    1) SUMMARY: Oral diphenhydramine, as well as other H1 antihistamines can be used as indicated (Lieberman et al, 2010).
    2) ADULT: 50 milligrams orally, or 10 to 50 mg intravenously at a rate not to exceed 25 mg/min or may be given by deep intramuscular injection. A total of 100 mg may be administered if needed. Maximum daily dosage is 400 mg (Prod Info diphenhydramine HCl intravenous injection solution, intramuscular injection solution, 2013).
    3) CHILD: 5 mg/kg/24 hours or 150 mg/m(2)/24 hours. Divided into 4 doses, administered intravenously at a rate not exceeding 25 mg/min or by deep intramuscular injection. Maximum daily dosage is 300 mg (Prod Info diphenhydramine HCl intravenous injection solution, intramuscular injection solution, 2013).
    5) MODERATE CASES
    a) EPINEPHRINE: INJECTABLE SOLUTION: It should be administered early in patients by IM injection. Using a 1:1000 (1 mg/mL) solution of epinephrine. Initial Dose: 0.01 mg/kg intramuscularly with a maximum dose of 0.5 mg in adults and 0.3 mg in children. The dose may be repeated every 5 to 15 minutes, if no clinical improvement. Most patients respond to 1 or 2 doses (Nowak & Macias, 2014).
    6) SEVERE CASES
    a) EPINEPHRINE
    1) INTRAVENOUS BOLUS: ADULT: 1 mg intravenously as a 1:10,000 (0.1 mg/mL) solution; CHILD: 0.01 mL/kg intravenously to a maximum single dose of 1 mg given as a 1:10,000 (0.1 mg/mL) solution. It can be repeated every 3 to 5 minutes as needed. The dose can also be given by the intraosseous route if IV access cannot be established (Lieberman et al, 2015). ALTERNATIVE ROUTE: ENDOTRACHEAL ADMINISTRATION: If IV/IO access is unavailable. DOSE: ADULT: Administer 2 to 2.5 mg of 1:1000 (1 mg/mL) solution diluted in 5 to 10 mL of sterile water via endotracheal tube. CHILD: DOSE: 0.1 mg/kg to a maximum of 2.5 mg administered as a 1:1000 (1 mg/mL) solution diluted in 5 to 10 mL of sterile water via endotracheal tube (Lieberman et al, 2015).
    2) INTRAVENOUS INFUSION: Intravenous administration may be considered in patients poorly responsive to IM or SubQ epinephrine. An epinephrine infusion may be prepared by adding 1 mg (1 mL of 1:1000 (1 mg/mL) solution) to 250 mL D5W, yielding a concentration of 4 mcg/mL, and infuse this solution IV at a rate of 1 mcg/min to 10 mcg/min (maximum rate). CHILD: A dosage of 0.01 mg/kg (0.1 mL/kg of a 1:10,000 (0.1 mg/mL) solution up to 10 mcg/min (maximum dose 0.3 mg) is recommended for children (Lieberman et al, 2010). Careful titration of a continuous infusion of IV epinephrine, based on the severity of the reaction, along with a crystalloid infusion can be considered in the treatment of anaphylactic shock. It appears to be a reasonable alternative to IV boluses, if the patient is not in cardiac arrest (Vanden Hoek,TL,et al).
    7) AIRWAY MANAGEMENT
    a) OXYGEN: 5 to 10 liters/minute via high flow mask.
    b) INTUBATION: Perform early if any stridor or signs of airway obstruction.
    c) CRICOTHYROTOMY: Use if unable to intubate with complete airway obstruction (Vanden Hoek,TL,et al).
    d) BRONCHODILATORS are recommended for mild to severe bronchospasm.
    e) ALBUTEROL: ADULT: 2.5 to 5 milligrams in 2 to 4.5 milliliters of normal saline delivered per nebulizer every 20 minutes up to 3 doses. If incomplete response administer 2.5 to 10 mg every 1 to 4 hours as needed, or 10 to 15 mg/hr by continuous nebulization as needed (National Heart,Lung,and Blood Institute, 2007).
    f) ALBUTEROL: CHILD: 0.15 milligram/kilogram (minimum 2.5 milligrams) per nebulizer every 20 minutes up to 3 doses. If incomplete response administer 0.15 to 0.3 milligram/kilogram (maximum 10 milligrams) every 1 to 4 hours as needed OR administer 0.5 mg/kg/hr by continuous nebulization (National Heart,Lung,and Blood Institute, 2007).
    8) MONITORING
    a) CARDIAC MONITOR: All complicated cases.
    b) IV ACCESS: Routine in all complicated cases.
    9) HYPOTENSION
    a) If hypotensive give 500 to 2000 milliliters crystalloid initially (20 milliliters/kilogram in children) and titrate to desired effect (stabilization of vital signs, mentation, urine output); adults may require up to 6 to 10 L/24 hours. Central venous or pulmonary artery pressure monitoring is recommended in patients with persistent hypotension.
    1) VASOPRESSORS: Should be used in refractory cases unresponsive to repeated doses of epinephrine and after vigorous intravenous crystalloid rehydration (Lieberman et al, 2010).
    2) DOPAMINE: Initial Dose: 2 to 20 micrograms/kilogram/minute intravenously; titrate to maintain systolic blood pressure greater than 90 mm Hg (Lieberman et al, 2010).
    10) H1 and H2 ANTIHISTAMINES
    a) SUMMARY: Antihistamines are second-line therapy and are used as supportive therapy and should not be used in place of epinephrine (Lieberman et al, 2010).
    1) DIPHENHYDRAMINE: ADULT: 25 to 50 milligrams via a slow intravenous infusion or IM. PEDIATRIC: 1 milligram/kilogram via slow intravenous infusion or IM up to 50 mg in children (Lieberman et al, 2010).
    b) RANITIDINE: ADULT: 1 mg/kg parenterally; CHILD: 12.5 to 50 mg parenterally. If the intravenous route is used, ranitidine should be infused over 10 to 15 minutes or diluted in 5% dextrose to a volume of 20 mL and injected over 5 minutes (Lieberman et al, 2010).
    c) Oral diphenhydramine, as well as other H1 antihistamines, can also be used as indicated (Lieberman et al, 2010).
    11) DYSRHYTHMIAS
    a) Dysrhythmias and cardiac dysfunction may occur primarily or iatrogenically as a result of pharmacologic treatment (epinephrine) (Vanden Hoek,TL,et al). Monitor and correct serum electrolytes, oxygenation and tissue perfusion. Treat with antiarrhythmic agents as indicated.
    12) OTHER THERAPIES
    a) There have been a few reports of patients with anaphylaxis, with or without cardiac arrest, that have responded to vasopressin therapy that did not respond to standard therapy. Although there are no randomized controlled trials, other alternative vasoactive therapies (ie, vasopressin, norepinephrine, methoxamine, and metaraminol) may be considered in patients in cardiac arrest secondary to anaphylaxis that do not respond to epinephrine (Vanden Hoek,TL,et al).

Enhanced Elimination

    A) HEMODIALYSIS
    1) It is unknown if hemodialysis would be effective in overdose; however, hemodialysis is not recommended given the low toxicity of these drugs.

Range Of Toxicity

Summary

    A) TOXICITY: A minimum toxic dose has not been established, and significant toxicity is not expected after an overdose. Ingestion of even large quantities should produce only minor GI symptoms (eg, nausea, vomiting, and diarrhea). THERAPEUTIC DOSE: Varies by agent. Topical application is mainly once or twice a day for 7 to 14 days.

Therapeutic Dose

    7.2.1) ADULT
    A) The following antifungals are available in a variety of formulations (eg, cream, lozenges, ointment, vaginal suppository) in the United States: Butaconazole, clotrimazole, econazole, efinaconazole, oxiconazole, sertaconazole, sulconazole, and tioconazole (Prod Info ERTACZO(R) topical cream, 2014; Goldust et al, 2013; Prod Info JUBLIA(R) 10% topical solution, 2014; Prod Info GYNAZOLE-1(R) vaginal cream, 2006; Prod Info clotrimazole troche oral lozenges, 2005; Prod Info ECONAZOLE NITRATE topical cream, 2013; Prod Info ECOZA topical foam, 2013; Prod Info OXISTAT(R) cream, lotion, 2004; Prod Info EXELDERM(R) topical cream, 2003; Prod Info EXELDERM(R) topical solution, 2003; Prod Info MONISTAT(R) vaginal ointment, 2001). Dosing and duration vary by agent.
    7.2.2) PEDIATRIC
    A) SPECIFIC SUBSTANCE
    1) The safety and efficacy of the following drugs have not been established in children: Butoconazole, efinaconazole, luliconazole, sulconazole, and tioconazole (Product Information , 1998; Prod Info LUZU topical cream, 2013; Prod Info JUBLIA(R) 10% topical solution, 2014; Prod Info GYNAZOLE-1(R) vaginal cream, 2006; Prod Info MONISTAT(R) vaginal ointment, 2001).
    2) The following antifungals are available in a variety of formulations (eg, cream, lozenges, ointment, vaginal suppository) in the United States: Butaconazole, clotrimazole, econazole, efinaconazole, oxiconazole, sertaconazole, sulconazole, and tioconazole (Prod Info ERTACZO(R) topical cream, 2014; Goldust et al, 2013; Prod Info JUBLIA(R) 10% topical solution, 2014; Prod Info GYNAZOLE-1(R) vaginal cream, 2006; Prod Info clotrimazole troche oral lozenges, 2005; Prod Info ECONAZOLE NITRATE topical cream, 2013; Prod Info ECOZA topical foam, 2013; Prod Info OXISTAT(R) cream, lotion, 2004; Prod Info EXELDERM(R) topical cream, 2003; Prod Info EXELDERM(R) topical solution, 2003; Prod Info MONISTAT(R) vaginal ointment, 2001). Dosing and duration vary by agent.

Maximum Tolerated Exposure

    A) ADULT
    1) Hepatic abnormalities were reported in 10% to 15% of 145 patients receiving oral clotrimazole for pulmonary mycosis in doses of 20 mg/kg 3 times a day. Elevations in AST, ALT, and bilirubin levels were noted (Weuta, 1974).
    B) PEDIATRIC
    1) Abnormal ECG findings were reported in an 8-year-old boy who received clotrimazole 70 mg/kg/day orally for a period of 45 days for pulmonary aspergilloma. ECG findings revealed electrical alternans and inverted T waves which were possibly drug-induced. Clotrimazole was discontinued but the abnormal ECG abnormalities persisted for a period of 5 weeks. No other toxicity was noted in this patient. ECG changes were probably NOT related to clotrimazole (Evans et al, 1971).

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) BIFONAZOLE
    1) LD50- (ORAL)MOUSE:
    a) 2629 mg/kg (RTECS , 2001)
    2) LD50- (SUBCUTANEOUS)MOUSE:
    a) >15 g/kg (RTECS , 2001)
    3) LD50- (ORAL)RAT:
    a) 1463 mg/kg (RTECS , 2001)
    4) LD50- (SUBCUTANEOUS)RAT:
    a) >10 g/kg (RTECS , 2001)
    B) BUTOCONAZOLE NITRATE
    1) LD50- (INTRAPERITONEAL)MOUSE:
    a) >1600 mg/kg (RTECS , 2001)
    2) LD50- (ORAL)MOUSE:
    a) >3200 mg/kg (RTECS , 2001)
    3) LD50- (INTRAPERITONEAL)RAT:
    a) 940 mg/kg (RTECS , 2001)
    4) LD50- (ORAL)RAT:
    a) 1720 mg/kg (RTECS , 2001)
    C) CLOTRIMAZOLE
    1) LD50- (INTRAPERITONEAL)MOUSE:
    a) 108 mg/kg (RTECS , 2001)
    2) LD50- (ORAL)MOUSE:
    a) 761 mg/kg (RTECS , 2001)
    3) LD50- (INTRAPERITONEAL)RAT:
    a) 445 mg/kg (RTECS , 2001)
    4) LD50- (ORAL)RAT:
    a) 708 mg/kg (RTECS , 2001)
    D) CROCONAZOLE HYDROCHLORIDE
    1) LD50- (INTRAPERITONEAL)MOUSE:
    a) 94 mg/kg (RTECS , 2001)
    2) LD50- (ORAL)MOUSE:
    a) 1150 mg/kg (RTECS , 2001)
    3) LD50- (ORAL)RAT:
    a) 2 g/kg (RTECS , 2001)
    4) LD50- (SKIN)RAT:
    a) >600 mg/kg (RTECS , 2001)
    E) ECONAZOLE NITRATE
    1) LD50- (ORAL)MOUSE:
    a) 463 mg/kg (RTECS , 2001)
    2) LD50- (ORAL)RAT:
    a) 668 mg/kg (RTECS , 2001)
    3) LD50- (SUBCUTANEOUS)RAT:
    a) 1360 mg/kg (RTECS , 2001)
    F) FENTICONAZOLE
    1) LD50- (INTRAPERITONEAL)MOUSE:
    a) 1191 mg/kg (RTECS , 2001)
    2) LD50- (ORAL)MOUSE:
    a) >3 g/kg (RTECS , 2001)
    3) LD50- (ORAL)RAT:
    a) >3 g/kg (RTECS , 2001)
    4) LD50- (SUBCUTANEOUS)RAT:
    a) >750 mg/kg (RTECS , 2001)
    G) OMOCONAZOLE NITRATE
    1) LD50- (ORAL)MOUSE:
    a) 4700 mg/kg (RTECS , 2001)
    H) OXICONAZOLE NITRATE
    1) LD50- (INTRAPERITONEAL)MOUSE:
    a) 595 mg/kg (RTECS , 2001)
    2) LD50- (ORAL)MOUSE:
    a) 2630 mg/kg (RTECS , 2001)
    3) LD50- (INTRAPERITONEAL)RAT:
    a) 630 mg/kg (RTECS , 2001)
    4) LD50- (ORAL)RAT:
    a) 2458 mg/kg (RTECS , 2001)
    I) SERTACONAZOLE
    J) SULCONAZOLE NITRATE
    1) LD50- (INTRAPERITONEAL)MOUSE:
    a) 810 mg/kg (RTECS , 2001)
    2) LD50- (ORAL)MOUSE:
    a) 2475 mg/kg (RTECS , 2001)
    3) LD50- (SUBCUTANEOUS)MOUSE:
    a) >4 g/kg (RTECS , 2001)
    4) LD50- (INTRAPERITONEAL)RAT:
    a) 735 mg/kg (RTECS , 2001)
    5) LD50- (ORAL)RAT:
    a) 1741 mg/kg (RTECS , 2001)
    6) LD50- (SUBCUTANEOUS)RAT:
    a) 4 g/kg (RTECS , 2001)
    K) TIOCONAZOLE
    1) LD50- (INTRAPERITONEAL)MOUSE:
    a) 508 mg/kg (RTECS , 2001)
    2) LD50- (ORAL)MOUSE:
    a) 1870 mg/kg (RTECS , 2001)
    3) LD50- (INTRAPERITONEAL)RAT:
    a) 730 mg/kg (RTECS , 2001)
    4) LD50- (ORAL)RAT:
    a) 770 mg/kg (RTECS , 2001)
    5) LD50- (SUBCUTANEOUS)RAT:
    a) >10 g/kg (RTECS , 2001)

Pharmacology Toxicology

Pharmacologic Mechanism

    A) These drugs are fungistatic and may be fungicidal, depending on concentration. Imidazoles inhibit biosynthesis of ergosterol or other sterols, damaging the fungal cell membrane and altering its permeability. As a result, loss of essential intracellular elements may occur (USP-DI(R), 2001; (Product Information , 2000a; Bennett, 1996).
    B) Imidazoles also inhibit biosynthesis of triglycerides and phospholipids by fungi. They inhibit oxidative and peroxidative enzyme activity, resulting in intracellular buildup of toxic concentrations of hydrogen peroxide, which may contribute to deterioration of subcellular organelles and cellular necrosis. In Candida albicans, imidazoles inhibit transformation of blastospores into invasive mycelial form (USP-DI(R), 2001; (Bennett, 1996).

Physicochemical

Physical Characteristics

    A) BIFONAZOLE is a white or almost white polymorphic crystalline powder. It is practically insoluble in water and sparingly soluble in dehydrated alcohol (Sweetman, 2007).
    B) BUTOCONAZOLE NITRATE is a white to off-white crystalline powder. It is practically insoluble in water; very slightly soluble in ethyl acetate, slightly soluble in chloroform, methylene chloride, acetone, and ethanol; and sparingly soluble in methanol (Prod Info GYNAZOLE-1(R) vaginal cream, 2006).
    C) CLOTRIMAZOLE is an odorless, white crystalline powder that is insoluble in water and soluble in ethanol (Prod Info LOTRISONE(R) topical cream, lotion, 2008).
    D) ECONAZOLE NITRATE is a white or practically white, crystalline powder, with a slight odor. It is very slightly soluble in water and in ether; slightly soluble in alcohol; sparingly soluble in chloroform; and soluble in methyl alcohol (Sweetman, 2007).
    E) EFINACONAZOLE topical solution is a clear, colorless to pale yellow solution (Prod Info JUBLIA(R) 10% topical solution, 2014).
    F) FENTICONAZOLE nitrate is a white or almost white, crystalline powder. It is practically insoluble in water; sparingly soluble in dehydrated alcohol; and freely soluble in dimethylformamide and in methyl alcohol (Sweetman, 2007).
    G) OXICONAZOLE NITRATE is a nearly white crystalline powder. It is soluble in methanol; sparingly soluble in ethanol, chloroform, and acetone; and very slightly soluble in water (Prod Info OXISTAT(R) topical cream, lotion, 2009).
    H) SERTACONAZOLE NITRATE is a white or almost white powder. It is practically insoluble in water, soluble in methanol, and sparingly soluble in alcohol and in methylene chloride (Prod Info ERTACZO(TM) topical cream, 2003).
    I) SULCONAZOLE NITRATE is a white to off-white crystalline powder. It is freely soluble in pyridine; slightly soluble in ethanol, acetone, and chloroform; and very slightly soluble in water with a melting point of about 130 degrees C (Prod Info EXELDERM(R) topical solution, 2009).
    J) TIOCONAZOLE is a white or almost white crystalline powder. It is very slightly soluble in water; freely soluble in alcohol; and very soluble in dichloromethane (Sweetman, 2007).

Molecular Weight

    A) BIFONAZOLE: 310.5 (Sweetman, 2007)
    B) BUTOCONAZOLE NITRATE: 474.79 (Prod Info GYNAZOLE-1(R) vaginal cream, 2006)
    C) CLOTRIMAZOLE: 344.84 (Prod Info LOTRISONE(R) topical cream, lotion, 2008)
    D) CROCONAZOLE HYDROCHLORIDE: 347.2 (Sweetman, 2007)
    E) ECONAZOLE NITRATE: 444.7 (Prod Info ECOZA topical foam, 2013)
    F) EFINACONAZOLE: 348.39 (Prod Info JUBLIA(R) 10% topical solution, 2014)
    G) FENTICONAZOLE NITRATE: 518.4 (Sweetman, 2007)
    H) LULICONAZOLE: 354.28 (Prod Info LUZU topical cream, 2013)
    I) OMOCONAZOLE NITRATE: 486.7 (Sweetman, 2007)
    J) OXICONAZOLE NITRATE: 492.15 (Prod Info OXISTAT(R) topical cream, lotion, 2009)
    K) SERTACONAZOLE NITRATE: 500.8 (Prod Info ERTACZO(TM) topical cream, 2003)
    L) SULCONAZOLE NITRATE: 460.77 (Prod Info EXELDERM(R) topical solution, 2009)
    M) TIOCONAZOLE: 387.7 (Sweetman, 2007)

References

General Bibliography

    1) Adetoro OO: Tioconazole in the management of recurrent vaginal candidosis during pregnancy in Ilorin, Nigeria. Curr Ther Res 1987; 41:647-650.
    2) Alomar C, Bassas S, & Casas M: Multi-centre double-blind trial on the efficacy and safety of sertaconazole 2% cream in comparison with miconazole 2% cream on patients suffering from cutaneous mycoses. Arzneimittelforschung 1992; 42:767-773.
    3) Anon: Clotrimazole (Lotrimin(R)) - a new topical antifungal drug. Med Let Drug Ther 1975; 17:77.
    4) Azcona O, Torrent J, & Verges J: Tolerance and kinetic behavior after single and repeated vaginal administration of sertaconazole cream and tablets in healthy volunteers. Curr Ther Res 1991; 49:1046-1060.
    5) Baes H: Contact sensitivity to miconazole with ortho-chloro cross-sensitivity to other imidazoles. Contact Dermatitis 1991; 24(2):89-93.
    6) Belli L, Galimberti R, & Negroni R: Treatment of superficial candidiasis with bifonazole 1% gel. Pharmatherapeutica 1985a; 4:102-105.
    7) Benfield P & Clissold SP: Sulconazole: a review of its antimicrobial activity and therapeutic use in superficial dermatomycoses. Drugs 1988; 35:143-153.
    8) Bennett JE: Antimicrobial agents. In Goodman and Gilman's the pharmacological basis of therapeutics. 9th ed, McGraw Hill, New York, NY, 1996, pp 1175-1190.
    9) Bradbeer CS, Mayhew SR, & Barlow D: Butoconazole and miconazole in treating vaginal candidiasis. Genitourin Med 1985; 61:270-272.
    10) Burgess MA & Bodey GP: Clotrimazole (Bay B 5097): in vitro and clinical pharmacological studies. Antimicrob Agents Chemother 1972; 2:423.
    11) Cartwright RY: Clotrimazole in the treatment of acute and "resistant" vaginal candidiasis. Postgrad Med J 1974; 50(suppl 1):90.
    12) Cooper SM & Shaw S: Contact allergy to clotrimazole: an unusual allergen. Contact Dermatitis 1999; 41(3):168.
    13) Czeizel AE, Toth M, & Rockenbauer M: No teratogenic effect after clotrimazole therapy during pregnancy. Epidemiology 1999; 10:437-440.
    14) Droegemueller W, Adamson DG, & Brown D: Three-day treatment with butoconazole nitrate for vulvovaginal candidiasis. Obstet & Gynecol 1984; 64:530-534.
    15) Duhm B: Pharmacokinetics of topically applied bisphenyl-(2-chlorophenyl)-1- imidazolyl-methand-14 C). Drugs Made in Germany 1972b; 15:99.
    16) Evans EGV, Watson DH, & Matthews NR: Pulmonary aspergillomata in a child treated with clotrimazole. Br Med J 1971; 4:599-600.
    17) Fachinformation: Fungisan(R), Omoconazolnitrat, Galderma Laboratorium GmbH, Freiburg, Germany, 1996.
    18) Fachinformation: Lomexin(R), fenticonazole nitrate, Gruenenthal GmbH, Stolberg, Germany, 1992.
    19) Faria A, Goncalo S, & Goncalo M: Allergic contact dermatitis from tioconazole. Contact Dermatitis 1996; 35:250-252.
    20) Farre M, Ugena B, & Badenas JM: Pharmacokinetics and tolerance of sertaconazole in man after repeated percutaneous administration. Arzneimittelforschung 1992; 42:752-754.
    21) Fioroni A, Terragni L, & Vannini P: Fenticonazole plasma levels during treatment with fenticonazole 2% cream and spray in patients with dermatomycoses. Curr Ther Res 1990; 47:997-1003.
    22) Franz TJ & Lehman P: Percutaneous absorption of sulconazole nitrate in humans. J Pharm Sci 1988; 77:489-491.
    23) Frerich W & Gad A: The frequency of candida infections in pregnancy and their treatment with clotrimazole. Curr Med Res Opin 1977; 4:640-644.
    24) Fricke U & Klaus W: Neue Arzneimittel 1991/92, Wissenschaftliche Verlagsgesellschaft mbH, Stuttgart, Germany, 1992.
    25) Fromtling RA: Overview of medically important antifungal azole derivatives. Clin Microbiol Rev 1988; 1:187-217.
    26) Galimberti R, Belli L, & Gatti JC: An open, multicentre assessment of the effectiveness of bifonazole in the treatment of tinea (pityriasis) versicolor. Pharmatherapeutica 1985; 4:109-112.
    27) Goldust M, Rezaee E, Masoudnia S, et al: Clinical study of sertaconazole 2% cream vs. hydrocortisone 1% cream in the treatment of seborrheic dermatitis. Ann Parasitol 2013; 59(3):119-123.
    28) Goormans E, Beek JM, & Declercq JA: Efficacy of econazole ('Gyno-Peraryl' 150) in vaginal candidosis during pregnancy. Curr Med Res Opin 1985; 9:371-377.
    29) Gorlero F, Sartani A, & Cordaro CI: Fenticonazole tissue levels after the application of 3 different dosage forms of vaginal ovules. Int J Clin Pharmacol Ther Toxicol 1988; 26:479-481.
    30) Haram K & Digranes A: Vulvovaginal candidiasis in pregnancy treated with clotrimazole. Acta Obstet Gynecol Scand 1978; 57:453-455.
    31) Hernandez-Perez E: A comparison between one and two weeks' treatment with bifonazole in pityriasis versicolor. J Am Acad Dermatol 1986; 14:561-564.
    32) Holt RJ: Recent developments in antimycotic chemotherapy. Infection 1974; 2:95.
    33) Huguenin-Dumittan SA: Massive left tuberculous pyothorax with bronchial fistula, responsive to drug therapy, followed by rapid invasion of aspergillosis: recovery after administration of a new oral antimycotic agent. Schweiz Med Wschr 1972; 102:118.
    34) Jacobson JB, Hajman AJ, & Wiese J: Butoconazole nitrate: 1% and 2% creams compare well with miconazole nitrate in vaginal candidiasis. Acta Obstet Gynecol Scand 1985; 64:241-244.
    35) Kalb RE & Grossman ME: Contact dermatitis to clotrimazole. Cutis 1985; 36:240-242.
    36) King CT, Rogers PD, & Cleary JD: Antifungal therapy during pregnancy. Clin Infect Dis 1998; 27:1151-1160.
    37) Kucers A & Bennett NMcK: The Use of Antibiotics, 3rd ed, William Heinemann Medical Books, Ltd, London, 1979.
    38) Lackner TE & Clissold SP: Bifonazole: a review of its antimicrobial activity and therapeutic use in superficial mycoses. Drugs 1989; 38:204-225.
    39) Lassus A, Forstrom S, & Salo O: A double-blind comparison of sulconazole nitrate 1% cream with clotrimazole 1% cream in the treatment of dermatophytoses. Br J Dermatol 1983; 108:195-198.
    40) Leiste D, Braun W, & Fegeler W: A double-blind clinical trial of fenticonazole (2%) spray versus naftifine (1%) spray in patients with cutaneous mycoses. Curr Med Res Opin 1989; 11:567-575.
    41) Lieberman P, Nicklas R, Randolph C, et al: Anaphylaxis-a practice parameter update 2015. Ann Allergy Asthma Immunol 2015; 115(5):341-384.
    42) Lieberman P, Nicklas RA, Oppenheimer J, et al: The diagnosis and management of anaphylaxis practice parameter: 2010 update. J Allergy Clin Immunol 2010; 126(3):477-480.
    43) Lund-Olesen K: Clotrimazole, plasma cortisol and rheumatoid arthritis. Curr Ther Res 1977; 21:704.
    44) Malchow H, Seybold D, & Lnage H: Successful treatment of candida sepsis with the oral antimycotic Bay b 5097. Deutsch Med Wschr 1972; 97:935-938.
    45) Maloley PA, Nelson E, & Montgomery HA: Severe reversible thrombocytopenia resulting from butoconazole cream. DICP Ann Pharmacother 1990; 24:143-144.
    46) Menz HP, Teltscher U, & Bayer C: Pharmacokinetics of clotrimazole, an oral antimycotic, in humans. Deutsch Med Wschr 1973; 98:1606.
    47) Michel G: New products. Croconazole hydrochloride. Drugs of Today 1993; 29(5):307-310.
    48) Midgley I, Biggs SR, & Hawkins DR: The metabolic fate of (3H) econazole in man. Xenobiotica 1981; 11:595-608.
    49) National Heart,Lung,and Blood Institute: Expert panel report 3: guidelines for the diagnosis and management of asthma. National Heart,Lung,and Blood Institute. Bethesda, MD. 2007. Available from URL: http://www.nhlbi.nih.gov/guidelines/asthma/asthgdln.pdf.
    50) Nowak RM & Macias CG : Anaphylaxis on the other front line: perspectives from the emergency department. Am J Med 2014; 127(1 Suppl):S34-S44.
    51) Patzschke K, Ritter W, & Siefert HM: Pharmacokinetic studies following systemic and topical administration of (14C)bifonazole in man. Arzneimittelforschung 1983; 33:745-750.
    52) Product Information : Physicians' Desk Reference : Clotrimazole 1% cream and vaginal inserts. Medical Economics, Inc. Montvale, NJ (Internet Version). Edition expires 2000a; provided by Truven Health Analytics Inc., Greenwood Village, CO.
    53) Product Information : Physicians' Desk Reference: Exelderm(R), sulconazole 1% cream and solution. Westwood-Squibb Pharmaceuticals, Princeton, NJ. Medical Economics, Inc. Montvale, NJ (Internet Version). Edition expires 1998; provided by Truven Health Analytics Inc., Greenwood Village, CO.
    54) Product Information : Physicians' Desk Reference: Mycelex(R) troches, clotrimazole oral troches (lozenges). Alza pharmaceuticals, Mountain View, CA. Medical Economics, Inc. Montvale, NJ (Internet Version). Edition expires 2000b; provided by Truven Health Analytics Inc., Greenwood Village, CO.
    55) Product Information : Physicians' Desk Reference: Spectazole(R), econazole 1% cream. Ortho-McNeil Pharmaceuticals, Raritan, NJ. Medical Economics, Inc. Montvale, NJ (Internet Version). Edition expires 2000; provided by Truven Health Analytics Inc., Greenwood Village, CO.
    56) Product Information: ECONAZOLE NITRATE topical cream, econazole nitrate 1% topical cream. IGI Labs, Inc. (per DailyMed), Buena, NJ, 2013.
    57) Product Information: ECOZA topical foam, econazole nitrate 1% topical foam. Quinnova Pharmaceuticals (per FDA), Jamison, PA, 2013.
    58) Product Information: ERTACZO(R) topical cream, sertaconazole nitrate 2% topical cream. Valeant Pharmaceuticals North America LLC (per FDA), Bridgewater, NJ, 2014.
    59) Product Information: ERTACZO(TM) topical cream, sertaconazole nitrate topical cream. Ortho-McNeil Pharmaceutical,Inc, Skillman, NJ, 2003.
    60) Product Information: EXELDERM(R) topical cream, sulconazole nitrate topical cream. Westwood Squibb, Buffalo, NY, 2003.
    61) Product Information: EXELDERM(R) topical solution, sulconazole nitrate topical solution. Ranbaxy, Jacksonville, FL, 2009.
    62) Product Information: EXELDERM(R) topical solution, sulconazole nitrate topical solution. Westwood-Squibb Pharmaceuticals, Inc, Princeton, NJ, 2003.
    63) Product Information: Femstat(R), butoconazole. Syntex Laboratories, Palo Alto, CA, 2000.
    64) Product Information: GYNAZOLE-1(R) vaginal cream, butoconazole nitrate vaginal cream. Ther-Rx Corp., St Louis, MO, 2006.
    65) Product Information: JUBLIA(R) 10% topical solution, efinaconazole 10% topical solution. Valent Pharmaceuticals North America LLC (per DailyMed), Bridgewater, NJ, 2014.
    66) Product Information: LOTRISONE(R) topical cream, lotion, clotrimazole and betamethasone dipropionate topical cream, lotion. Schering Corporation, Kenilworth, NJ, 2008.
    67) Product Information: LUZU topical cream, luliconazole 1% topical cream. Medicis (per FDA), Bridgewater, NJ, 2013.
    68) Product Information: MONISTAT(R) vaginal ointment, tioconazole vaginal ointment. Personal Products Company, Skillman, NJ, 2001.
    69) Product Information: MYCELEX(R)-G vaginal tablets, clotrimazole vaginal tablets. Bayer Corporation, West Haven, CT, 1995.
    70) Product Information: OXISTAT(R) cream, lotion, oxiconazole nitrate cream, oxiconazole nitrate lotion. GlaxoSmithKline, Pittsburgh, PA, 2004.
    71) Product Information: OXISTAT(R) topical cream, lotion, oxiconazole nitrate 1% topical cream, lotion. PharmaDerm, Melville, NY, 2009.
    72) Product Information: Oxistat(R), oxiconazole. Glaxo Pharmaceuticals, Research Triangle Park, NC, 2000.
    73) Product Information: TRIVAGIZOLE 3(TM) vaginal cream, clotrimazole vaginal cream. Taro Pharmaceuticals Inc, Bramalea, Ontario, 2000.
    74) Product Information: Vagistat(R), tioconazole. Mead Johnson Laboratories, Princeton, NJ, 1994.
    75) Product Information: clotrimazole troche oral lozenges, clotrimazole troche oral lozenges. Paddock Laboratories,Inc, Minneapolis, MN, 2005.
    76) Product Information: diphenhydramine HCl intravenous injection solution, intramuscular injection solution, diphenhydramine HCl intravenous injection solution, intramuscular injection solution. Hospira, Inc. (per DailyMed), Lake Forest, IL, 2013.
    77) RTECS : Registry of Toxic Effects of Chemical Substances. National Institute for Occupational Safety and Health. Cincinnati, OH (Internet Version). Edition expires July/31/2001; provided by Truven Health Analytics Inc., Greenwood Village, CO.
    78) Raulin C & Frosch PJ: Contact allergy to imidazole antimycotics. Contact Derm 1989; 18:76-80.
    79) Raulin C & Frosch PJ: Contact allergy to oxiconazole. Contact Derm 1987; 16:39-40.
    80) Sartani A, Cordaro CI, & Panconesi E: A multicenter trial with a new imidazole derivative, fenticonazole, in superficial fungal skin infections. Curr Ther Res 1988; 43:1194-1203.
    81) Sawyer PR, Brogden RN, & Pinder RM: Clotrimazole: a review of its antifungal activity and therapeutic efficacy. Drugs 1975; 9:424-447.
    82) Shono M, Hayashi K, & Sugimoto R: Allergic contact dermatitis from croconazole hydrochloride. Contact Dermatitis 1989; 21(4):225-227.
    83) Spiekermann PH & Young MD: Clinical evaluation of clotrimazole: a broad-spectrum antifungal agent. Arch Dermatol 1976; 112:350.
    84) Steinmann A, Mayer G, & Breit R: Allergic contact dermatitis from croconazole without cross-sensitivity to clotrimazole and bifonazole. Contact Derm 1996; 35:255-256.
    85) Svendsen E, Lie S, & Gunderson TH: Comparative evaluation of miconazole, clotrimazole and nystatin in the treatment of candidal vulvo-vaginitis. Curr Ther Res 1978; 23:666-672.
    86) Sweetman, S: Martindale: The Complete Drug Reference. London: Pharmaceutical Press. Electronic Version, Thomson Healthcare. Greenwood Village, CO. 2007.
    87) Tan CG, Good CS, & Milne LJR: A comparative trial of six day therapy with clotrimazole and nystatin in pregnant patients with vaginal candidiasis. Postgrad Med 1974; 50(suppl 1):102-105.
    88) Tanenbaum L, Anderson C, & Rosenberg MJ: 1% sulconazole cream v 2% miconazole cream in the treatment of tinea versicolor: a double-blind, multicenter study. Arch Dermatol 1984; 120:216-219.
    89) Vanden Hoek,TL; Morrison LJ; Shuster M; et al: Part 12: Cardiac Arrest in Special Situations 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. American Heart Association. Dallas, TX. 2010. Available from URL: http://circ.ahajournals.org/cgi/reprint/122/18_suppl_3/S829. As accessed 2010-10-21.
    90) Veronese M, Barzaghi D, & Bertoncini A: Mutagenicity studies on fenticonazole, a new antifungal imidazole derivative. Arzneimittelforschung 1981; 31:2142-2144.
    91) Veronese M, Barzaghi D, & Bertoncini A: The salmonella mutagenicity assay on fenticonazole, a new antifungal imidazole derivative. Arzneimittelforschung 1981a; 31:2140-2142.
    92) Wahlberg JE: Irritation threshold, tolerance and cross reactions with clotrimazole applied to skin. Postgrad Med J 1974; 50:53-54.
    93) Weuta H: Clinical investigations with systemic administration of clotrimazole: pharmacokinetics, effectiveness and tolerance. Arzneimittelforschung 1974; 24:540.
    94) Wiest W & Ruffmann R: Short-term treatment of vaginal candidiasis with fenticonazole ovules: a three-dose schedule comparative trial. J Int Med Res 1987; 15:319-325.
    95) del Palacio Hernanz A, Lopez Gomez S, & Diez LI: Short course bifonazole therapy in pityriasis versicolor. Clin Exp Dermatol 1987; 12:270-272.