ATC Class:G01AF15
VA Class:GU300
Butoconazole nitrate, an imidazole derivative, is a synthetic azole antifungal agent.1, 2, 3
Uncomplicated Vulvovaginal Candidiasis
Butoconazole nitrate 2% vaginal cream is used intravaginally for the treatment of vulvovaginal candidiasis.1, 4, 6, 7, 24, 29, 30, 31, 50, 51 Butoconazole nitrate may be used for self-medication in otherwise healthy, nonpregnant women who have been previously diagnosed by a clinician and are having a recurrence of similar symptoms.29, 47
Prior to initial use of butoconazole in a woman who has signs and symptoms of uncomplicated vulvovaginal candidiasis, the diagnosis should be confirmed either by demonstrating yeast or pseudohyphae with direct microscopic examination of vaginal discharge (saline or 10% potassium hydroxide [KOH] wet mount or Gram stain) or by culture.1, 4, 5, 6, 24, 29, 31 Identifying Candida by culture in the absence of symptoms is not an indication for antifungal treatment since approximately 10-20% of women harbor Candida or other yeasts in the vagina.29 When an adequate response is not achieved following a course of butoconazole nitrate therapy for vulvovaginal candidiasis or if there is recurrence of symptoms within 2 months, appropriate microbiologic studies should be performed to confirm the diagnosis and rule out infection caused by other pathogens before another course of antifungal therapy is initiated.1, 29
Up to 75% of women reportedly have at least one episode of vulvovaginal candidiasis and 40-45% have 2 or more episodes during their lifetime,29, 36, 37 but a small percentage of women (up to 5%) have recurrent vulvovaginal candidiasis (i.e., 4 or more episodes of symptomatic vulvovaginal candidiasis in a year).29, 36, 40 While certain factors may precipitate a sporadic attack of vulvovaginal candidiasis and have been associated with an increased risk for recurrent vulvovaginal candidiasis (e.g., uncontrolled diabetes mellitus, pregnancy, oral contraceptive use, corticosteroid or other immunosuppressive therapy, immunodeficiency, use of intravaginal sponges or devices, repeated courses of topical or systemic antibacterial agents),36, 37, 39, 40 these factors are not present in most women who have recurrent episodes.29, 35, 41
Azole antifungals (imidazole and triazole derivatives) are considered the drugs of choice for the treatment of vulvovaginal candidiasis.7, 29, 34, 35, 36, 37, 39, 40, 41, 50 The US Centers for Disease Control and Prevention (CDC) and other clinicians recommend that uncomplicated vulvovaginal candidiasis (defined as vulvovaginal candidiasis that is mild to moderate, sporadic or infrequent, most likely caused by Candida albicans , and occurring in immunocompetent women) should be treated with an intravaginal azole antifungal (e.g., butoconazole, clotrimazole, miconazole, terconazole, tioconazole) given in appropriate single-dose or short-course regimens or, alternatively, oral fluconazole given in a single-dose regimen.7, 29, 34, 36, 37, 40, 41, 50 These regimens generally have been associated with clinical and mycologic cure rates of 80-90% in otherwise healthy, nonpregnant women with uncomplicated infections,29, 36, 37, 40, 41 and there is no clear evidence that any one intravaginal azole antifungal regimen is superior to any other intravaginal azole regimen available for the treatment of these infections.7, 36, 37, 41 While intravaginal nystatin also can be used for the treatment of uncomplicated vulvovaginal candidiasis, it generally is less effective than intravaginal azole antifungals.7, 29 A longer duration of intravaginal therapy (i.e., 7-14 days) or use of an oral azole antifungal generally is necessary for the treatment of complicated vulvovaginal candidiasis, including recurrent and severe disease.7, 29, 35, 36, 37, 40, 45, 50 Complicated vulvovaginal candidiasis is defined as infections that are recurrent or severe, caused by Candida other than C. albicans , or are occurring in women who have underlying medical conditions such as pregnancy, uncontrolled diabetes mellitus, debilitation, or immunosuppression.29, 48, 50 (See Complicated and Recurrent Vulvovaginal Candidiasis under Uses: Vulvovaginal Candidiasis.)
Vulvovaginal candidiasis usually is not acquired through sexual activity,29, 46 and treatment of sexual partner(s) is not recommended but may be considered in women who have recurrent infections.29, 38, 46 However, male sexual partners who have symptomatic balanitis or penile dermatitis may benefit from treatment with a topical antifungal agent to relieve symptoms.29
Cure rates resulting from therapy with butoconazole nitrate vaginal cream are similar to those achieved with clotrimazole vaginal tablets4 or miconazole nitrate vaginal cream.5, 6, 24 In several comparative studies, butoconazole nitrate 2% cream applied intravaginally once daily for 3 days appeared to be as effective as clotrimazole 200 mg administered as vaginal tablets once daily for 3 days4 or as effective as miconazole nitrate 2% cream administered intravaginally once daily for 6 or 7 days.6, 24 In another study comparing butoconazole nitrate 1 and 2% cream and miconazole nitrate 2% cream applied intravaginally once daily in a 6-day regimen, cure rates for these preparations were similar, although butoconazole nitrate 2% was slightly more effective.5 In comparative studies, single-dose therapy using butoconazole nitrate 2% cream (Gynazole-1®) was as effective as single-dose therapy using a 500-mg tablet of clotrimazole (no longer commercially available in the US).1
Butoconazole nitrate reportedly produces clinical cures (i.e., complete absence of vulvovaginal burning, itching, swelling, erythema, excoriation, and/or ulceration and substantial decreases in vaginal discharge) in approximately 75-80% of nonpregnant women with vulvovaginal candidiasis.5, 24, 26 Microbiologic cure rates of 80-95% and 80-85% have been reported about 8 days posttreatment in nonpregnant women receiving once-daily application of butoconazole nitrate 2% cream for 3 or 6 days.4, 6, 24 The clinical and microbiologic cure rates following a 3-day regimen of butoconazole nitrate appear to be similar to those following a 6-day regimen.24 Microbiologic cure rates have decreased by about 15-20% secondary to recurrence or reinfection in nonpregnant and pregnant patients who were followed for approximately 30-40 days after a course of butoconazole nitrate therapy.4, 5, 6
Butoconazole has been used with good results in women with vulvovaginal candidiasis during oral contraceptive use.4, 5, 24 Although oral contraceptive use has been associated with an increased incidence of vulvovaginal candidiasis and frequently recurring infection,18 cure rates reported with butoconazole therapy in several studies in patients using oral contraceptive agents concomitantly did not differ substantially from those in women using other methods of contraception or not practicing contraception.4, 5, 24
Complicated and Recurrent Vulvovaginal Candidiasis
Optimum regimens for the treatment of recurrent vulvovaginal candidiasis (usually defined as 4 or more episodes of symptomatic vulvovaginal candidiasis in a year) have not been established.29, 36, 37, 39, 40, 41 Although each individual episode caused by C. albicans may respond to usual short-course intravaginal antifungal regimens or a single-dose of oral fluconazole, a longer duration of initial therapy may be necessary to achieve mycologic remission and chronic maintenance therapy may be necessary to prevent relapse.29, 48, 49, 50 The CDC recommends use of an initial intensive regimen consisting of 7-14 days of an intravaginal azole antifungal or a 3-dose regimen of oral fluconazole (100-, 150-, or 200-mg doses given every third day for a total of 3 doses) followed by a maintenance antifungal regimen (given for 6 months).29 For the maintenance regimen, the CDC recommends oral fluconazole (100-, 150-, or 200-mg doses once weekly).29 If this oral regimen cannot be used, some clinicians recommend intravaginal clotrimazole (200 mg twice weekly or 500 mg once weekly) or other intravaginal treatments used intermittently.29 These maintenance regimens can be effective in reducing recurrent infections; however, 30-50% of women will have recurrent disease once maintenance therapy is discontinued.29
The response rate to short-course antifungal regimens is lower in patients with severe vulvovaginal candidiasis (i.e., extensive vulvar erythema, edema, excoriation, and fissure formation) and either a 2-dose regimen of oral fluconazole (150 mg repeated 3 days later) or 7-14 days therapy with an intravaginal azole antifungal is recommended for these infections.29 These more prolonged regimens may also be necessary for the treatment of vulvovaginal candidiasis in women with underlying debilitating medical conditions (e.g., those with uncontrolled diabetes mellitus or those receiving corticosteroid therapy).29
For the treatment of vulvovaginal candidiasis during pregnancy, the CDC and others recommend use of a 7-day regimen of an intravaginal azole antifungal.29, 50 (See Cautions: Pregnancy, Fertility, and Lactation.)
Vulvovaginal candidiasis may occur more frequently and may be more severe in women with human immunodeficiency virus (HIV) infection than in women without HIV infection and these infections have been recognized as an early manifestation of acquired immunodeficiency syndrome (AIDS) in women.32, 41 While optimum therapy for recurrent vulvovaginal candidiasis in HIV-infected women has not been established, there is no evidence to date that these women have a lower response rate to the intravaginal or oral antifungal regimens usually recommended for the treatment of vulvovaginal candidiasis.29, 41 Therefore, the CDC and other clinicians recommend that treatment of vulvovaginal candidiasis in HIV-infected women be the same as that in women without HIV infection.29, 41, 46, 49, 50
Recurrent vulvovaginal candidiasis rarely may be caused by resistant strains of C. albicans or, more commonly, by other Candida with reduced susceptibility to azole antifungals (e.g., C. glabrata ).39, 40, 41, 42, 43, 44, 45 It has been suggested that repeated treatment of recurrent vulvovaginal candidiasis with intravaginal azole antifungals and widespread and/or injudicious use of these agents for self-medication of vulvovaginal candidiasis may favor the selection of Candida resistant to azole antifungals.40, 41, 42, 43, 44, 45 Optimum therapy for the treatment of vulvovaginal candidiasis caused by Candida with reduced susceptibility to azole antifungals has not been determined to date.41 For the treatment of vulvovaginal candidiasis caused by Candida other than C. albicans , the CDC recommends 7-14 days of therapy with an antifungal agent other than fluconazole; if recurrence occurs, intravaginal boric acid (600-mg capsule once daily for 2 weeks) is recommended.29, 48 Referral to a specialist is advised.29
Butoconazole nitrate is administered intravaginally as a 2% cream.1, 47 Butoconazole nitrate vaginal cream is for intravaginal administration only and should not be administered orally; contact with the eyes should be avoided.47
Butoconazole nitrate vaginal cream should be used for self-medication of recurrent vulvovaginal candidiasis only in otherwise healthy, nonpregnant women previously diagnosed by a clinician.47
Patients should be instructed how to use the vaginal applicator and should be given a copy of the instructions provided by the manufacturer.1, 47
Butoconazole nitrate vaginal cream contains a mineral oil base that may weaken rubber or latex products, including condoms or vaginal contraceptive diaphragms,1, 47 and use of such products within 72 hours following treatment with intravaginal butoconazole is not recommended.1
Uncomplicated Vulvovaginal Candidiasis
The usual dosage of Gynazole-1® for adults is a single applicatorful (approximately 5 g) of butoconazole nitrate 2% cream (100 mg of the drug total) administered intravaginally as a single dose.1, 29
For self-medication in the treatment of vulvovaginal candidiasis in nonpregnant women and children 12 years of age or older, the usual dosage of Mycelex®-3 is a one applicatorful (approximately 5 g) of butoconazole nitrate 2% cream (100 mg of the drug total) administered intravaginally once daily at bedtime for 3 consecutive days.29, 47
Individuals should be instructed to contact a clinician if the infection persists after the 3-day course of therapy or recurs within 2 months.47
Complicated Vulvovaginal Candidiasis
For the treatment of recurrent vulvovaginal candidiasis caused by Candida albicans , the CDC and other clinicians recommend an initial intensive regimen (7-14 days of an intravaginal azole or 3-dose regimen of oral fluconazole) to achieve mycologic remission, followed by an appropriate maintenance regimen (6-month regimen of once-weekly oral fluconazole or, alternatively, an intravaginal azole given intermittently).7, 29, 35, 36, 37, 41, 46, 48, 50
For the treatment of vulvovaginal candidiasis that is severe, caused by Candida other than C. albicans , or occurring in women with underlying medical conditions, the CDC and other clinicians recommend 7-14 days of an intravaginal azole.29, 50
HIV-infected patients with vulvovaginal candidiasis generally should receive the same regimen recommended for other patients;29, 41, 46, 49 however, some experts recommend a treatment duration of 3-7 days in such patients.49 Although a maintenance regimen of an intravaginal azole can be considered for those with recurrent episodes,49 routine primary or secondary prophylaxis (long-term suppressive or chronic maintenance therapy) is not usually recommended.29, 49
Butoconazole nitrate for intravaginal use is generally well tolerated.4 Adverse effects were reported in about 2% of patients during clinical studies evaluating 3- or 6-day regimens of the drug.4, 5 When a single-dose regimen of intravaginal butoconazole (Gynazole-1®) was evaluated in clinical studies, 5.7% of patients reported adverse effects; although several patients reporting such effects discontinued the study, adverse effects were considered treatment-related in only 1% of patients.1
Adverse effects reported with intravaginal butoconazole include vulvovaginal burning,1, 4, 5, 24 itching,1, 24 soreness and swelling,1, 24 and/or pelvic or abdominal pain or cramping.1 Headache,5 urinary frequency and burning,24 and vulvovaginal discharge,6 irritation,4 stinging,6 and odor6 occurred rarely during therapy with the drug.
Although hepatocellular dysfunction has occurred during systemic treatment with imidazole-derivative antifungal agents (i.e., ketoconazole),13, 14 this adverse effect has not been reported to date following intravaginal butoconazole nitrate therapy.5, 26
Precautions and Contraindications
Butoconazole nitrate cream is contraindicated in patients with known hypersensitivity to the drug or any ingredient in the formulation.1
Butoconazole should be used for self-medication of vulvovaginal candidiasis only in otherwise healthy, nonpregnant women who have been previously diagnosed by a clinician and are having a recurrence of similar symptoms.47 Patients using butoconazole for self-medication should be advised to contact a clinician if they develop a fever, abdominal pain, or a foul-smelling vaginal discharge, or if symptoms of vulvovaginal candidiasis do not improve within 3 days or recur within 2 months.29, 47
Patients should be instructed to contact their physician if symptoms of irritation occur or persist or sensitization occurs during butoconazole therapy.26 If irritation or sensitization occurs and appears to be drug related, butoconazole should be discontinued.26
Appropriate microbiologic studies should be performed to confirm the diagnosis and rule out infection caused by nonsusceptible pathogens when an adequate response is not achieved following a course of butoconazole therapy.1
Patients should be given a copy of the patient information provided by the manufacturer.1, 47 They should be instructed not to rely on condoms or diaphragms to prevent sexually transmitted diseases or pregnancy within 72 hours after butoconazole nitrate therapy since the cream may damage these devices and result in protective failure.1, 47
Butoconazole nitrate vaginal cream should not be applied to the eye nor administered orally.47 Patients receiving butoconazole nitrate vaginal cream should be instructed to contact their physician or local poison control center immediately if they accidentally ingest the vaginal cream.
Patients should be instructed to contact a clinician if symptoms persist after therapy since more prolonged treatment with the drug may be required or a condition requiring alternative therapy may be present.29, 47 Patients also should be advised to consult a clinician if manifestations of vulvovaginitis recur within 2 months.29, 47 Recurrent infections, especially those that are difficult to eradicate, may be a early sign of human immunodeficiency virus (HIV) infection.1
Safety and efficacy of butoconazole nitrate in children have not been established.1 The drug should not be used for self-medication in children younger than 12 years of age.47
Mutagenicity and Carcinogenicity
In vitro tests have not shown butoconazole nitrate to be mutagenic.1, 10, 15 Long-term animal studies to determine carcinogenic potential of the drug have not been performed to date.1
Pregnancy, Fertility, and Lactation
Reproduction studies in pregnant rats receiving 6 mg/kg of butoconazole nitrate intravaginally daily (3-7 times the usual human intravaginal dose) during the period of fetal organogenesis have shown an increased fetal resorption rate and decreased litter size, but evidence of teratogenicity was not observed.1 Adverse reproductive effects have not been reported following oral administration of butoconazole nitrate to pregnant rats at dosages up to 50 mg/kg daily (5 times the usual human dosage based on mg/m2) throughout organogenesis.1 Orally administered dosages of 100, 300, or 750 mg/kg daily (10, 30, or 75 times, respectively, the usual human dosage) in pregnant rats have resulted in fetal malformations (e.g., abdominal wall defects, cleft palate), but maternal stress was evident at these higher dosages and may have been a contributing factor.1 Teratogenic effects were not observed in rabbits receiving oral butoconazole nitrate doses associated with maternal stress (i.e., 150 mg/kg; 24 times the usual human dosage based on mg/m2).1 Like other imidazole antifungal agents, butoconazole has been associated with dystocia in rats when therapy with the drug was extended through parturition; however, this effect has not been observed in rabbits.1
There are no adequate and controlled studies to date with butoconazole nitrate in pregnant women during the first trimester.1 The manufacturer states that intravaginal butoconazole should be used during pregnancy only if the potential benefits justifies the possible risks to the fetus.1 The CDC and others state that a 7-day regimen of an intravaginal azole antifungal can be used, if necessary, for the treatment of vulvovaginal candidiasis in pregnant women.29, 50
It is not known whether butoconazole nitrate affects fertility in humans.26 Reproduction studies in rabbits or rats receiving oral butoconazole nitrate dosages up to 30 or 100 mg/kg daily, respectively, have not revealed evidence of impaired fertility.1
Since it is not known whether butoconazole is distributed into milk, the drug should be used with caution in nursing women.1
There have been no reports to date of overdosage with butoconazole nitrate in humans.26 The oral LD50 of butoconazole nitrate in mice and male rats is greater than 3200 mg/kg and in female rats is 17,20 mg/kg; the intraperitoneal LD50 of the drug was greater than 1600 or 940 mg/kg in mice or rats, respectively.15
Butoconazole usually is fungistatic in action3, 8, 16, 22 but may have growth phase-dependent fungicidal activity at high concentrations or against very susceptible organisms.1, 3, 8, 16, 22
Like other imidazole derivatives, butoconazole nitrate presumably exerts its antifungal activity by altering cellular membranes,1, 8, 9, 17, 22 resulting in increased membrane permeability, secondary metabolic effects, and growth inhibition.1, 9, 17, 22 Although the exact mechanism of action of butoconazole nitrate has not been fully determined,1, 22 it has been suggested that the fungistatic activity of the drug may result from interference with ergosterol synthesis probably via inhibition of C-14 demethylation of sterol intermediates (e.g., lanosterol).3, 9, 16, 17 Like some other imidazole derivatives (e.g., miconazole), the fungicidal activity of butoconazole at high concentrations may result from a direct physiochemical effect of the drug on the fungal cell.8, 9, 16 This effect may involve hydrophobic interactions between the drug and unsaturated fatty acid components of the membrane.9, 16
Butoconazole has some antibacterial activity against gram-positive organisms, but this effect cannot be explained on the basis of inhibition of ergosterol synthesis since bacteria generally do not contain membrane sterols.9, 16 It has been suggested that the antibacterial effect of butoconazole and other imidazole derivatives may be similar to the physiochemical effect of these agents on fungi9, 16 or may involve other metabolic sites.22
Butoconazole nitrate is active against many fungi, including dermatophytes and yeasts.2, 15, 17, 23 The drug also has in vitro activity against some gram-positive bacteria.15, 23
Results of in vitro butoconazole nitrate susceptibility tests are method dependent, and MIC values vary depending on the culture medium used, the presence of serum, and inoculum size.2 In addition, currently available in vitro tests may not accurately reflect the in vivo susceptibility of some fungi (especially Candida ).27
Butoconazole is active in vitro against Trichophyton concentricum , T. mentagrophytes , T. rubrum , T. tonsurans , Epidermophyton floccosum , Microsporum canis , and M. gypseum .15, 23 Most susceptible strains of these fungi are inhibited in vitro by butoconazole nitrate concentrations of 5 mcg/mL or less.15, 23 In vitro on a weight basis, butoconazole's activity against dermatophytes appears to be similar to that of clotrimazole, econazole, ketoconazole, miconazole, and tioconazole.2 Butoconazole also is active in vitro against Aspergillus 2 and Cryptococcus ,23 but the drug appears to be less active than other imidazole antifungal agents against Aspergillus .2
A wide range of butoconazole MIC values have been reported for Candida .15, 23 In one in vitro study, the MIC of butoconazole for C. albicans , C. glabrata , and C. tropicalis was 1-10 mcg/mL;23 however, in another study, C. albicans required butoconazole concentrations of up to 30 mcg/mL for growth inhibition.15 In vitro on a weight basis, butoconazole's activity against C. albicans , C. tropicalis , and other candidal species appears to be similar to that of clotrimazole, econazole, ketoconazole, miconazole, nystatin, sulconazole, and tioconazole.2 Butoconazole nitrate is active against experimentally induced C. albicans vaginal infection in mice.15, 23 In vivo on a weight basis in mice, butoconazole nitrate has been reported to have greater activity than miconazole against C. albicans .15, 23
Butoconazole is also active in vitro against Staphylococcus aureus , Enterococcus faecalis (formerly Streptococcus faecalis ), and S. pyogenes .15, 23
Cross resistance can occur among the azole antifungal agents.2 Some strains of C. albicans with known in vivo resistance to other imidazole antifungal agents also appear to be resistant to butoconazole in vitro.2
Small amounts of butoconazole nitrate are slowly absorbed systemically when the drug is administered intravaginally.1, 4 Following intravaginal administration of approximately 5 g of radiolabeled butoconazole nitrate 2% cream (approximately 100 mg of the drug total) in healthy women, peak plasma concentrations 24 hours after administration have ranged from 19-44 ng/mL.4 Radioactivity was apparent in plasma 2-8 hours after intravaginal administration and persisted for 4-5 days.4 Based on limited pharmacokinetic data, it is estimated that about 1.7% (range: 1.3-2.2%) of an intravaginal dose of butoconazole nitrate reaches systemic circulation.1
Distribution of butoconazole nitrate into body tissues and fluids following intravaginal administration has not been determined.
Butoconazole nitrate crosses the blood-brain barrier and the placenta in animals following IV and intravaginal administration, respectively, but it is not known whether this occurs in humans.
It is not known whether butoconazole is distributed into milk.1
The metabolic fate of butoconazole nitrate following intravaginal administration has not been fully characterized, but systemically absorbed drug appears to be extensively metabolized, probably in the liver.4
The systemically absorbed fraction of an intravaginal dose of butoconazole nitrate appears to be excreted in approximately equal proportions in urine and feces.4 Approximately 2.7 and 2.8% of an intravaginal dose of the drug reportedly is excreted in urine and feces, respectively, within 4-7 days, principally as unidentified metabolites; unchanged drug is not detectable.4
Butoconazole nitrate, an imidazole derivative, is a synthetic azole antifungal agent.1, 2, 3 Butoconazole is structurally related to other imidazole-derivative azole antifungals (e.g., clotrimazole, econazole, ketoconazole, miconazole, oxiconazole, sulconazole, tioconazole).1, 2, 3 Butoconazole nitrate occurs as a white to off-white, crystalline powder and is practically insoluble in water and slightly soluble in alcohol.1
For vaginal use, butoconazole nitrate is commercially available as a cream in a water-washable emollient base; methylparaben and propylparaben are added as preservatives.1
Butoconazole nitrate vaginal cream should be stored at 25°C, but may be exposed to temperatures of 15-30°C.1 Exposure to temperatures exceeding 30°C1, 47 and freezing47 should be avoided.
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Vaginal | Cream | 2% | Gynazole-1® (available with prefilled, disposable applicators) | Ther-Rx |
Mycelex®-3 (available with or without disposable applicators) | Bayer |
AHFS® Drug Information. © Copyright, 1959-2025, Selected Revisions July 1, 2009. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, MD 20814.
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46. Reviewers' comments (personal observations) on Tioconazole 84:04.08.
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