VA Class:GU300
ATC Class:D01AC07
Tioconazole, an imidazole derivative, is a synthetic azole antifungal agent.2, 3, 49, 65
Tioconazole is used intravaginally for the treatment of uncomplicated vulvovaginal candidiasis.1, 2, 3, 4, 10, 56, 75, 108, 123, 124, 126, 127, 128 Tioconazole also has been used topically for the treatment of a variety of dermatophytoses†, 9, 13, 14, 15, 16, 26, 27, 40, 41, 42, 43, 44, 55, 80, 88, 89, 98, 99 superficial mycoses†, 13, 14, 16, 42, 43, 89, 98 and cutaneous candidal infections†;13, 14, 15, 16, 26, 41, 42, 43, 44, 55, 58 however, tioconazole preparations for topical administration to the skin are not commercially available in the US.
Uncomplicated Vulvovaginal Candidiasis
Tioconazole 6.5% vaginal ointment is used for the treatment of uncomplicated vulvovaginal candidiasis in a single-dose regimen.1, 2, 108, 123, 124, 127, 128 Prior to initial use of tioconazole, 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 and other pathogens commonly associated with vulvovaginitis should be ruled out by appropriate methods.2, 125 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.108 The commercially available tioconazole 6.5% vaginal ointment 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.1, 72, 108, 123, 124
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,72, 75, 76, 108 but a small percentage of women (up to 5%) have recurrent vulvovaginal candidiasis (i.e., 4 or more episodes of symptomatic vulvovaginal candidiasis each year).75, 93, 108 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),72, 75, 76, 92, 93, 108 these factors are not present in most women who have recurrent episodes.57, 72, 74, 104, 108
Azole antifungals (imidazole and triazole derivatives) are considered the drugs of choice for the treatment of vulvovaginal candidiasis.4, 30, 74, 75, 76, 92, 93, 104, 108, 127, 128 The US Centers for Disease Control and Prevention (CDC) and other clinicians generally 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) 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.4, 30, 75, 76, 93, 102, 104, 108, 127, 128 These regimens generally have been associated with clinical and mycologic cure rates of 80-90% in otherwise healthy, nonpregnant women with uncomplicated infections,54, 75, 76, 93, 104, 108 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.75, 76, 104 While intravaginal nystatin also can be used for the treatment of uncomplicated vulvovaginal candidiasis, it generally is less effective than intravaginal azole antifungals.4, 108 A longer duration of therapy (i.e., 7-14 days) with an intravaginal or oral azole antifungal generally is necessary for the treatment of complicated vulvovaginal candidiasis, including recurrent and severe disease.10, 74, 75, 76, 93, 102, 108, 109, 127, 128 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.108, 127, 128 (See Complicated and Recurrent Vulvovaginal Candidiasis under Uses: Vulvovaginal Candidiasis.)
Results of several controlled clinical studies in otherwise healthy, nonpregnant women with uncomplicated vulvovaginal candidiasis indicate that a single dose of tioconazole 6.5% vaginal ointment results in a clinical cure (i.e., clearance of symptoms of vulvovaginal candidiasis such as discharge, irritation, and burning) in 90-96% and a mycologic cure in 77-81% of women at early follow-up.2, 10 At late follow-up, the clinical and mycologic cure rates were 71-90 and 54-77%, respectively.2, 10 In a study in otherwise healthy, nonpregnant women randomized to receive a single dose of tioconazole 6.5% vaginal ointment or a 3-day regimen of intravaginal clotrimazole (200 mg as intravaginal tablets once daily), the single-dose intravaginal tioconazole regimen was at least as effective as the 3-day intravaginal clotrimazole regimen.2, 10
Single-dose tioconazole is one of several single-dose azole antifungal regimens included in current recommendations for the treatment of uncomplicated vulvovaginal candidiasis.19, 20, 74, 75, 76, 92, 102, 104, 108 These regimens ensure compliance and usually are well tolerated.19, 20, 54, 74, 75, 76, 78, 92, 102, 104, 108 In addition, results of controlled clinical studies indicate that a single dose of tioconazole 6.5% vaginal ointment, a single 500-mg clotrimazole vaginal tablet (no longer commercially available in the US), or a single 150-mg oral dose of fluconazole generally are at least as effective as 3-day intravaginal azole antifungal regimens recommended for the treatment of uncomplicated vulvovaginal candidiasis.2, 10, 19, 20, 54, 78, 92, 118, 119 Efficacy of single-dose intravaginal antifungal regimens may result in part from the fact that therapeutic concentrations of the drugs remain in vaginal fluid for several days after the dose.2, 29, 73, 82 However, further study is needed to determine whether there is any clinically important difference in relapse rates between single-dose and other short-term (i.e., less than 7 days) antifungal regimens.76, 117
If an adequate response is not achieved following a single intravaginal dose of tioconazole, appropriate microbiologic studies (e.g., direct microscopic examination of KOH wet mount and/or culture) should be performed to confirm the diagnosis.1, 108 Other pathogens commonly associated with vulvovaginitis should be ruled out by appropriate methods before additional antifungal therapy is initiated.1, 108 In a study evaluating the efficacy of a second repeat dose of tioconazole 6.5% vaginal ointment in patients with vulvovaginal candidiasis who failed to respond to a prior dose of the drug, a mycologic cure was attained in 73% of patients at early follow-up and 50% of patients were still cured at late follow-up.2
Vulvovaginal candidiasis usually is not acquired through sexual activity,72, 108, 117 and treatment of sexual partner(s) is not recommended but may be considered in women who have recurrent infections.72, 79, 108, 117 However, male sexual partners who have symptomatic balanitis or penile dermatitis may benefit from treatment with a topical antifungal to relieve symptoms.108
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.72, 75, 76, 92, 93, 104, 108 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.108 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).108 For the maintenance regimen, the CDC recommends oral fluconazole (100-, 150-, or 200-mg doses once weekly).108 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.108 These maintenance regimens can be effective in reducing recurrent infections; however, 30-50% of women will have recurrent disease once maintenance therapy is discontinued.108
While a single-dose tioconazole regimen has been used for the treatment of vulvovaginal candidiasis in some pregnant women†, 2, 5, 17, 21, 84, 86 safety and efficacy of tioconazole during pregnancy have not been established.1, 2 (See Cautions: Pregnancy, Fertility, and Lactation.) In addition, for the treatment of vulvovaginal candidiasis during pregnancy, the CDC recommends use of a 7-day regimen of an intravaginal azole antifungal.108
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.104, 112 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.104, 108 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.104, 108, 117, 126, 127
Dermatophytoses and Cutaneous Candidiasis
Although tioconazole preparations for topical administration to the skin are not commercially available in the US, tioconazole has been used effectively in various formulations (e.g., 1 or 2% cream, 1% lotion, 1% powder) for the topical treatment of certain dermatophytoses†, 13, 14, 15, 16, 26, 40, 41, 42, 43, 44, 55, 58, 80, 88, 89, 98, 99 including tinea capitis,13, 14, 15, 16, 27 tinea corporis,13, 14, 15, 16, 27, 42 tinea cruris,13, 14, 15, 16, 27, 42 tinea manuum,13, 14, 16, 42 and tinea pedis,9, 14, 15, 88 caused by Epidermophyton floccosum , Microsporum audouini , M. canis , Trichophyton rubrum , or T. mentagrophytes .
Tioconazole has been used topically as a 28% solution (with undecylenic acid) (not commercially available in the US) for the treatment of tinea unguium† (onychomycosis) caused by T. rubrum , Hendersonula toruloidea , or Acremonium .40, 80, 99
Tioconazole has been used topically as a 1 or 2% cream for the treatment of cutaneous and mucocutaneous infections caused by C. albicans , including intertrigo, diaper rash, and paronychia†.13, 14, 15, 16, 26, 41, 42, 43, 44, 55, 58 Like other azole antifungals used topically on the skin (e.g., clotrimazole, econazole, ketoconazole, miconazole, oxiconazole, sulconazole), tioconazole has an advantage over some other topical antifungal agents (e.g. nystatin, tolnaftate) in the treatment of mixed infections or for empiric treatment pending identification of the causative organism since it is active against both dermatophytes and yeasts.3, 16, 27, 32, 53, 64
Although tioconazole preparations for topical administration to the skin are not commercially available in the US, tioconazole has been effective when used topically as a 1 or 2% cream or lotion for the treatment of pityriasis (tinea) versicolor† caused by Malassezia furfur ( Pityrosporum orbiculare or P. ovale ).13, 14, 16, 42, 43, 89, 98 Pityriasis (tinea) versicolor generally can be treated topically with an imidazole-derivative azole antifungal (e.g., clotrimazole, econazole, ketoconazole, miconazole, oxiconazole, sulconazole), an allylamine antifungal (e.g., terbinafine), ciclopirox olamine, or certain other topical therapies (e.g., selenium sulfide 2.5%).120, 121, 122 However, an oral antifungal (e.g., itraconazole, ketoconazole) may be indicated, with or without a topical antifungal, in patients who have extensive or severe infections or who fail to respond to or have frequent relapses with topical therapy.120, 121
Based on evidence from in vitro studies that tioconazole has some activity against Trichomonas vaginalis , the drug has been used intravaginally as a 2% cream (not commercially available in the US) in a limited number of women for the treatment of trichomoniasis†.22, 66, 85 While the overall clinical and parasitologic cure rate in these women 7 days after a 3-day regimen of once daily intravaginal tioconazole was 70-95%,22, 66, 85 efficacy and safety of tioconazole for the treatment of vaginal trichomoniasis have not been established.75, 102, 108 The CDC and other clinicians currently recommend oral metronidazole or oral tinidazole as the treatment of choice for trichomoniasis.75, 108 (See Uses: Trichomoniasis, in Metronidazole 8:30.92.)
Tioconazole has been effective when administered topically to the skin in the form of a 1 or 2% cream (not commercially available in the US) for the treatment of superficial bacterial skin infections such as erythrasma† caused by Corynebacterium minutissimum 41, 44, 55 or impetigo† caused by staphylococci, streptococci, or gram-negative bacilli.41, 58
Tioconazole is administered intravaginally as a 6.5% ointment.1, 108, 123, 124 Although the following dosage forms are not commercially available in the US, tioconazole also has been administered intravaginally as a 100- or 300-mg vaginal suppository†, 3, 5, 17, 18, 21 100-mg vaginal tablet†, 86 6% vaginal ointment,3, 11, 17, 84 or 2% vaginal cream†;3, 22, 66, 85, 86 applied topically to the skin as a 1 or 2% cream†3, 5, 13, 14, 15, 16, 26, 27, 41, 42, 43, 44, 55, 58, 88, 98 or 1% lotion†;3, 89 applied topically to the nails as a 28% lotion†;3, 45, 46, 50, 80, 89, 99 and applied topically to the feet as a 1% powder†.3, 9
Commercially available prefilled single-dose applicators containing tioconazole 6.5% vaginal ointment are intended for intravaginal administration only.1 Contact with eyes should be avoided.1
Tioconazole 6.5% vaginal ointment should be used for self-medication of recurrent vulvovaginal candidiasis only in otherwise healthy, nonpregnant women previously diagnosed by a clinician.1, 108, 123, 124
Patients should be instructed how to use the vaginal applicators and should be given a copy of the instructions provided by the manufacturer.117 The applicator should be opened just prior to administration to prevent contamination.1, 123, 124
Tioconazole 6.5% vaginal ointment contains a petrolatum base that may interact with rubber or latex products, including condoms or vaginal contraceptive diaphragms, and alternative methods of contraception should be used during the first 72 hours after an intravaginal dose of the drug.1, 124
Tioconazole vaginal ointment may be administered during menstruation,1, 56, 72, 117 but sanitary napkins should be used instead of vaginal tampons;1, 56, 72, 123, 124 some clinicians suggest that use of the vaginal ointment be delayed until after the menstrual flow has ceased.117
Uncomplicated Vulvovaginal Candidiasis
For self-medication or supervised therapy in the treatment of vulvovaginal candidiasis in nonpregnant adults and children 12 years of age or older, the contents of one prefilled applicator of tioconazole 6.5% vaginal ointment (approximately 4.6 grams of ointment containing 300 mg of tioconazole) should be inserted intravaginally high in the vaginal vault at bedtime.1, 123, 124
A single intravaginal dose of tioconazole 6.5% ointment generally is effective,1, 2, 3, 108 but complete relief may not occur on the day of treatment.123, 124 Most women experience some relief within 1 day and complete relief of symptoms within 7 days.123, 124 If symptoms of vulvovaginal candidiasis do not improve within 3 days, persist for more than 7 days, or recur within 2 months after the dose, self-medication should be discontinued and the patient should consult a clinician.1, 108, 123, 124 Appropriate microbiologic studies (e.g., direct microscopic examination of potassium hydroxide microscopic wet mount and/or culture) should be performed to confirm the diagnosis, and other pathogens commonly associated with vulvovaginitis should be ruled out by appropriate methods.1, 108
HIV-infected patients with uncomplicated vulvovaginal candidiasis generally should receive the same regimen recommended for other patients;108, 126 however, some experts recommend a treatment duration of 3-7 days in such patients.126 Although a maintenance regimen of an intravaginal azole can be considered for those with recurrent episodes,126 routine primary or secondary prophylaxis (long-term suppressive or chronic maintenance therapy) is not usually recommended.108, 126
Complicated Vulvovaginal Candidiasis
For the treatment of recurrent vulvovaginal candidiasis caused by Candida albicans , the US Centers for Disease Control and Prevention (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).108, 127
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.108, 127
Tioconazole usually is well tolerated when administered intravaginally1, 2, 3, 5, 10, 11, 22, 56, 66, 84, 85, 86 or applied topically to the skin.13, 14, 15, 16, 26, 27, 43, 44, 55, 89, 98 The most frequent adverse reactions to intravaginal tioconazole are transient local effects,1, 2, 3, 10, 11, 66, 86 but these generally are mild to moderate in severity and rarely require symptomatic treatment.1, 2, 3, 10, 86
Local Effects and Sensitivity Reactions
Vulvovaginal burning,1, 2, 10, 86, 123 vaginitis,1 and pruritus1, 2, 10, 86, 123 are the most common adverse effects reported with intravaginal tioconazole. These local effects generally have been reported in 5-6% of women who received a single dose of the commercially available tioconazole 6.5% vaginal ointment for the treatment of vulvovaginal candidiasis.1, 2 In one small study, however, vulvovaginal irritation or pruritus occurred in up to 30% of patients who received a single intravaginal dose of the ointment; symptoms ranged from mild to severe in intensity and lasted an average of 18 hours.10 Other local effects reported in less than 1-2%1, 2 of patients who received a single dose of tioconazole 6.5% vaginal ointment in clinical studies include vulvovaginal irritation or burning sensation,1, 2, 10 vulvovaginal disorder,1 vulvovaginal desquamation,1 vaginal pain,1, 2, 10 vulvar edema or swelling,1, 2, 10 vaginal discharge,1 vaginal dryness,1 rash,1 and dyspareunia.1 Some of these local effects (i.e., pruritus, vaginal discharge, vulvovaginal disorder, dyspareunia) also are symptoms of vulvovaginal candidiasis, and it may be difficult to differentiate those that are related to the infection from those that may be related to the drug.10, 76
Topical application to the skin of tioconazole 1 or 2% cream (not commercially available in the US) has resulted in local effects similar to those reported with intravaginal application of the drug (e.g., transient, mild to moderate stinging, burning, and pruritus at the site of application).41, 42, 55, 88, 98 Rash, including mild maculopapular erythematous rash, also has occurred rarely following topical application of tioconazole to the skin.15, 55
It has been suggested that burning or irritation reported following intravaginal or topical application of tioconazole or other imidazole-derivative azole antifungals may reflect an irritant or contact sensitivity.104, 117 Contact dermatitis has been reported following topical application of tioconazole to the skin as a 1 or 2% cream or topical application of the drug to the nails as a 28% solution (not commercially available in the US).45, 46, 47, 48, 50, 51, 100 Contact dermatitis also has been reported following topical application of other imidazole-derivative azole antifungals (e.g., clotrimazole, econazole, miconazole, oxiconazole, sulconazole).47, 49, 113, 114 Cross-sensitization appears to occur among the imidazole derivatives; however, cross-sensitivity is unpredictable.45, 46, 47, 48, 49, 50, 51, 100, 113 While some patients with positive reactions to patch testing with tioconazole have had negative reactions to patch testing with clotrimazole, econazole, ketoconazole, miconazole, oxiconazole, and/or sulconazole,45, 46, 47, 48, 49, 50, 51, 100 other patients with positive reactions to tioconazole have had positive reactions to one or more of these other imidazole derivatives.45, 47, 49, 51, 100 The fact that patients with contact sensitivity to one imidazole-derivative azole antifungal may be sensitive to other similar drugs should be considered.45, 46, 47, 48, 49, 50, 51, 100 (See Cautions: Precautions and Contraindications.)
Adverse systemic effects have been reported occasionally in patients receiving intravaginal tioconazole.1, 86 Headache has been reported in 5%,1 infection in 3%,1 and abdominal pain in 2% of patients receiving a single dose of tioconazole 6.5% vaginal ointment.1 In addition, dysuria,1 nocturia,1, 2 pharyngitis,1 and rhinitis1 have been reported in less than 2% of patients receiving a single intravaginal dose of the drug.1
Transient, minor increases (less than twice the upper limit of normal) in serum concentrations of LDH, AST (SGOT), and ALT (SGPT) have been reported in less than 2% of patients receiving a single intravaginal dose of tioconazole in clinical studies.2
Precautions and Contraindications
Tioconazole is contraindicated in patients who are hypersensitive to the drug, other imidazole-derivative azole antifungals, or any ingredient in the formulation.1, 117
Tioconazole 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.1, 72, 108, 123, 124 Patients using tioconazole for self-medication should be advised to contact a clinician if symptoms of vulvovaginal candidiasis do not improve within 3 days, persist for more than 7 days, or recur within 2 months of the dose.1, 72, 108, 123, 124 Patients also should be advised to contact a clinician if symptoms of irritation or sensitization occur or persist after administration of the drug.1
Tioconazole should not be used for self-medication in women with diabetes mellitus or human immunodeficiency virus (HIV) infection, unless otherwise directed by a clinician.1 The CDC and other clinicians recommend that the treatment of vulvovaginal candidiasis in HIV-infected women should be the same as that in women without HIV infection.104, 108, 117 Patients should be advised not to use tioconazole and to contact their clinician if they think they are pregnant, have been exposed to HIV, or have abdominal pain, fever (higher than 37.8°C), chills, nausea, vomiting, or diarrhea.1, 123, 124 While recurrent vulvovaginal candidiasis may be a sign of pregnancy or serious underlying condition such as diabetes mellitus or HIV infection, most women with recurrent vulvovaginal candidiasis have no discernible risk factors.1, 108, 117
Because the commercially available tioconazole 6.5% vaginal ointment contains a petrolatum base that may interact with rubber or latex products such as condoms or vaginal contraceptive diaphragms, patients should be instructed not to use such products during the first 72 hours after a tioconazole dose.1, 108, 123, 124 Douching also should be avoided.10, 123, 124 Tioconazole vaginal ointment may be administered during menstruation,1, 56, 72, 117 but sanitary napkins should be used instead of vaginal tampons;1, 56, 72, 123, 124 some clinicians suggest that use of the vaginal ointment be delayed until after the menstrual flow has ceased.117
Safety and efficacy of tioconazole in pediatric patients younger than 12 years of age have not been established.1, 123, 124
Mutagenicity and Carcinogenicity
Animal and in vitro studies have not shown tioconazole to be mutagenic at the chromosomal or subchromosomal level.2, 83, 125 Tioconazole was not mutagenic when tested in vitro in Salmonella typhimurium , Saccharomyces cerevisiae , or Escherichia coli .2 No evidence of mutagenicity was observed when tioconazole was tested in vitro for chromosomal breaks in the human lymphocyte test or in cytogenetic studies in mice.2, 83
Long-term animal studies have not been performed to date to evaluate the carcinogenic potential of tioconazole.2, 125
Pregnancy, Fertility, and Lactation
There are no adequate and controlled studies evaluating use of intravaginal tioconazole in pregnant women, and the drug should be used during pregnancy only when the potential benefits justify the possible risks to the fetus.1, 2 A single dose of the commercially available tioconazole 6.5% vaginal ointment has been used in a limited number of pregnant women for the treatment of vulvovaginal candidiasis†, 2 and a single-dose of other tioconazole preparations not commercially available in the US (i.e., 2% vaginal cream, 100-mg vaginal tablet, 300-mg vaginal suppository, 6% vaginal ointment) have been used effectively to treat uncomplicated vulvovaginal candidiasis in pregnant women.2, 5, 17, 21, 84, 86 In most cases, the tioconazole dose was administered during the second or third trimester of pregnancy,2, 17, 21, 84, 86 but some women received the dose during the first trimester.2, 86 There generally were no apparent adverse effects on the pregnancy, delivery, or fetus following a single intravaginal dose of tioconazole;2, 5, 17, 21, 84, 86 however, there have been a few reports of adverse pregnancy outcomes (i.e., spontaneous abortion, breech delivery, premature birth).2 While these effects do not appear to be drug-related, it is difficult to distinguish drug- from disease-related effects.2, 21 The optimal regimen for the treatment of vulvovaginal candidiasis in pregnant women has not been identified, and further study is needed to evaluate safety and efficacy of single-dose regimens in these women.117 If treatment of vulvovaginal candidiasis is considered necessary in pregnant women, the US Centers for Disease Control and Prevention (CDC) and some clinicians recommend use of an intravaginal azole antifungal given for 7 days.72, 74, 93, 104, 108, 127
Reproduction studies in rats using oral tioconazole hydrochloride in dosages of 55-165 mg/kg daily during the period of organogenesis did not reveal evidence of adverse effects on fetal viability or growth, and there was no evidence of major structural anomalies in offspring.83, 125 While there was evidence of a drug-related increase in the incidence of dilated ureters, hydroureters, and hydronephrosis in the fetuses of these rats, these effects were transient and were no longer evident in the pups at 21 days of a 83, 125 these effects did not occur in rats following intravaginal administration of tioconazole 2% cream in a dosage of 10 mg/kg daily.125 Similar studies in rabbits using oral tioconazole dosages as high as 165 mg/kg daily or intravaginal 2% cream in a dosage of 2-3 mg/kg daily during organogenesis did not reveal evidence of embryotoxic or teratogenic effects.83, 125
In rats, when tioconazole administration was extended through parturition, the drug caused dystocia, prolonged gestation, and in utero deaths and resulted in an increase in the number of stillborn pups and a decrease in pup survival;36, 83, 125 pups that survived developed normally.83 These adverse effects on parturition occurred only when the drug was given orally in dosages exceeding 20 mg/kg daily or intravaginally in dosages exceeding 9 mg/kg daily during the last third of pregnancy,2, 36, 83, 95, 96, 125 and did not occur at lower oral or intravaginal dosages, when tioconazole was terminated before the last third of pregnancy, or when high oral dosage (150 mg) was confined to a few days before delivery.2, 83 No effect on parturition was noted in pregnant rabbits given oral tioconazole at dosages of 50 mg/kg daily during the last 10 days of pregnancy.2, 83, 125 Similar effects on parturition (e.g., dystocia, prolonged gestation) also have been reported in animal studies with high doses of other imidazole-derivative azole antifungals (e.g., econazole, ketoconazole, miconazole, sulconazole).36, 95, 96, 97, 115
It is not known whether tioconazole affects fertility in humans.125 In male rats, oral tioconazole hydrochloride in dosages up to 150 mg/kg daily did not affect fertility; however, there was evidence of preimplantation loss in female rats receiving the drug orally at dosages exceeding 35 mg/kg daily.125
Since it is not known whether tioconazole is distributed into milk, women should temporarily discontinue breast-feeding while they are receiving the drug.1, 2, 117
Since only small amounts of tioconazole are absorbed systemically following intravaginal administration,1, 2 drug interactions are unlikely in patients receiving the single-dose intravaginal regimen used in the treatment of vulvovaginal candidiasis.117 While results of animal studies indicate that tioconazole may induce hepatic cytochrome P-450 isoenzymes and the drug therefore theoretically could induce the metabolism of drugs metabolized by these enzymes,61, 63 it is unlikely that such drug interactions could occur with intravaginal tioconazole.117
Results of clinical studies indicate that efficacy of intravaginal tioconazole is not affected by concomitant use of oral contraceptives.1
Limited information is available on the acute toxicity of tioconazole in humans.117
Animal studies in mice, rats, and rabbits involving topical application of tioconazole to the skin or oral, intraperitoneal, or intravaginal administration of the drug generally have not revealed evidence of systemic toxicity.2, 83 However, acute toxicity studies in monkeys using oral tioconazole dosages of 100-150 mg/kg daily induced occasional vomiting, weight loss, and reversible liver changes (i.e., hepatomegaly and elevated serum transaminase and isocitrate dehydrogenase concentrations).83 Results of animal studies indicate that tioconazole, like some other imidazole-derivative azole antifungals (e.g., clotrimazole, miconazole), can induce hepatic cytochrome P-450 isoenzymes.61, 63 Reversible hepatomegaly accompanied by ultrastructural and biochemical changes characteristic of hepatic microsomal enzyme induction occurred in rats receiving oral tioconazole for 3 months,83 and hepatotoxicity also was evident in hamsters given the drug in a dosage of 50 mg/kg daily.61
If accidental ingestion of tioconazole vaginal ointment occurs, a clinician or poison control center should be contacted.1
Tioconazole usually is fungistatic in action, but may have growth phase- independent fungicidal activity at high concentrations or against very susceptible organisms.2, 7, 8, 37, 39, 59, 81
The antifungal activity of tioconazole, like that of most other imidazole-derivative azole antifungals (e.g., butoconazole, clotrimazole, econazole, ketoconazole, miconazole, oxiconazole, sulconazole) and triazole-derivative azole antifungals (e.g., fluconazole, itraconazole, terconazole), appears to involve several different mechanisms.2, 37, 38, 59, 62, 67, 68, 81 While the azole antifungals have some antifungal effects (especially those related to fungistatic activity) that are common to the entire group, some of the drugs have additional mechanisms of action that distinguish them from other azoles.39, 62, 67, 68, 81
The fungistatic activity of azole antifungals, including tioconazole, appears to result from interference with ergosterol synthesis, the principal sterol needed for incorporation into areas of newly synthesized fungal cell membranes.12, 59, 69 The nitrogen group contained in azole antifungal agents binds to the heme iron of the cytochrome P-450 isoenzyme 14-α-demethylase in susceptible fungi, thereby inhibiting the binding of lanosterol to the enzyme.12, 59, 62, 67, 69, 81, 90, 111 In actively growing yeast and dermatophyte cells, C-14 methylated sterols (e.g., 14-methylfecosterol, obtusifoliol, lanosterol) accumulate and cell membrane concentrations of ergosterol are decreased; these changes in sterol cell membrane composition disturb the structure and function of phospholipids in the cell membranes, causing changes in permeability, cell wall synthesizing enzymes (chitin), and growth rates.59, 62, 68, 69, 77, 81, 90, 111 The selectivity of azole antifungal agents for pathogenic organisms compared with host (mammalian) cells appears to depend on the relative affinities of the various drugs for mammalian versus fungal cytochrome P-450 sterol demethylases.81, 90
Like some other imidazole derivatives (e.g., butoconazole, clotrimazole, miconazole, sulconazole), tioconazole can exhibit fungicidal activity at high concentrations apparently as the result of direct physiochemical effects on the fungal cell membrane.2, 12, 37, 39, 59, 60, 67, 70, 81, 83 Studies using Candida albicans exposed to high tioconazole concentrations (15-100 mcg/mL) indicate that the rapid fungicidal activity is probably the result of direct interaction with lipid bilayers of the cell membrane causing leakage of intracellular ATP, ions, and other cytoplasmic material, and subsequent cell lysis.2, 12, 37, 39, 59, 60, 67, 70, 81, 83 At concentrations similar to those necessary for inhibition of sterol synthesis, tioconazole decreases ATP intracellular concentrations without causing accumulation of ATP in the extracellular fluid.38, 59, 67, 90 While the fungicidal activity of some azole antifungals (e.g., butoconazole, miconazole, sulconazole) appears to be a growth phase-dependent effect, tioconazole can exhibit fungicidal activity against Candida when the cells are in the stationary phase.2, 3, 7, 8, 39 However, tioconazole is most active against cells in the early logarithmic phase.8
There is some evidence from in vitro studies that the fungicidal activity of tioconazole may be pH dependent and may occur only at neutral pH.2, 7, 60, 90 Although the pH of vaginal secretions from women with vulvovaginal candidiasis generally is less than 4.5,72, 108 this acidic environment does not appear to have any clinically important effect on the antifungal activity of intravaginal tioconazole used for the treatment of this infection since the drug's fungistatic activity is not affected by pH.7, 117
In vitro studies on the morphologic effects of tioconazole on yeast indicate that the drug affects yeast-mycelium transformation by preventing the development of germ tubes or partially reducing the germ tube length and subsequent hyphal extension.2, 3, 35, 67, 70, 81 There may be a delay in effects on hyphal growth rate which may be due to the fact that preexisting pools of ergosterol must be depleted by the yeast cells before the effects of tioconazole are noted.12, 35, 81 Similar to some other imidazoles (e.g., clotrimazole, ketoconazole, miconazole), tioconazole affects the morphologic development of dermatophytes by reducing the swelling of arthrospores and micronidia and subsequent germ tube formation.2, 3, 33, 35, 67 The clinical relevance of these effects on yeast and dermatophyte cell growth remains to be determined.2, 90
Tioconazole, like some other azole antifungal agents, has some antibacterial activity;3, 52, 87 however, this effect cannot be explained on the basis of inhibition of ergosterol synthesis since bacteria generally do not contain membrane sterols.116 It has been suggested that the antibacterial effects of azole antifungals may be similar to the direct physiochemical effect of these agents on fungi and may involve interactions with unsaturated fatty acids in bacterial cell membranes.116 While fungi and many gram-positive bacteria may contain substantial amounts of free fatty acids, mammalian cells and gram-negative bacteria generally contain little or none.116
Tioconazole is active against many fungi, including most yeasts and dermatophytes.1, 3, 64 The drug also has some in vitro activity against certain aerobic gram-positive and gram-negative bacteria,3, 53, 87 Trichomonas ,3, 22 and Chlamydia .22
Like other azole antifungals (imidazole and triazole derivatives), results of in vitro tioconazole susceptibility tests are method dependent, and minimum inhibitory concentrations (MICs) vary depending on the culture medium used, incubation temperature and time, pH, inoculum, and presence of serum.3, 7, 12, 22, 23, 24, 31, 32, 33, 34, 38, 52, 59, 60, 77, 81, 110 In addition, currently available in vitro tests do not necessarily reflect the in vivo susceptibility of some fungi (especially Candida ).3, 24, 32, 34, 35, 71, 110 Optimal methods for antifungal agent in vitro susceptibility testing have been difficult to identify and are still being investigated.110, 111
Tioconazole is active in vitro against most strains of Candida 2, 23 and dermatophytes2, 23, 43, 44, 54, 64, 103 and also has some activity against other fungi, including Aspergillus 3, 23, 87 and Cryptococcus neoformans .3, 23, 24, 64
In vitro, tioconazole concentrations of 0.06-12.5 mcg/mL generally inhibit susceptible stains of C. albicans ,2, 23, 24, 25, 43, 44, 62 C. glabrata (formerly Torulopsis glabrata ),2, 24, 101 C. krusei ,2, 24 C. parapsilosis ,2, 24 C. pseudotropicalis ,2, 24 and C. tropicalis .2
Tioconazole is active in vitro against most pathogenic dermatophytes, including Epidermophyton floccosum ,3, 43, 44, 53, 64 E. stockdaleae ,53 Microsporum canis ,3, 23, 44, 64 M. gypseum ,3, 23, 64 Trichophyton mentagrophytes ,3, 23, 43, 44, 64 T. rubrum ,3, 23, 43, 44, 54, 103 and T. tonsurans .3, 64 These dermatophytes generally are inhibited in vitro by tioconazole concentrations of 0.1-6.25 mcg/mL.3, 23, 43, 44, 64
Tioconazole is active in vitro against some aerobic gram-positive and gram-negative bacteria, but is inactive against most anaerobic bacteria.3, 52, 87 In vitro, tioconazole concentrations of 0.4-16 mcg/mL generally inhibit Gardnerella vaginalis (formerly Haemophilus or Corynebacterium vaginalis ),3, 87 and concentrations of 1-8 mcg/mL generally inhibit Corynebacterium minutissimum , Enterococcus faecalis (formerly Streptococcus faecalis ),87 Staphylococcus aureus ,87 S. epidermidis ,87 and some streptococci.3, 87
Tioconazole also has some in vitro active against gram-negative bacteria, including Helicobacter pylori ,52 H. ducreyi ,87 Moraxella catarrhalis (formerly Branhamella catarrhalis ),87 Neisseria gonorrhoeae ,87 and N. meningitidis .87 These organisms generally are inhibited in vitro by tioconazole concentrations of 2-16 mcg/mL.52, 87
While tioconazole generally is inactive against anaerobic bacteria (including Lactobacillus ) that are important in maintaining normal flora and pH of the vagina,2, 87 the drug does have some in vitro activity against Mobiluncus .87
There is some evidence from in vitro studies that tioconazole may have some activity against Trichomonas vaginalis ,3, 22 Lymphogranuloma venereum ,3 and Chlamydia trachomatis .3
Strains of Candida albicans , C. glabrata , C. krusei , C. tropicalis , and C. parapsilosis that are resistant to tioconazole or have decreased susceptibility to the drug have been identified.2, 31, 32, 34, 90, 101, 111
Several mechanisms for decreased susceptibility to tioconazole have been suggested, including reduced intracellular accumulation of the drug as the result of defective lipids or sterols in the fungal membrane or active efflux of the drug or mutation of fungal 14-α-demethylase leading to diminished affinity for the enzyme.81, 90, 103, 111
Tioconazole-resistant fungi may be cross resistant to other azole antifungals.31, 32, 34, 90, 111 Clinical isolates of C. albicans , including some obtained from patients with chronic mucocutaneous candidiasis who had received long-term therapy with azole antifungals, have been found to have decreased susceptibility to several imidazole derivatives (butoconazole, clotrimazole, econazole, ketoconazole, miconazole, oxiconazole, sulconazole, tioconazole) and triazole derivatives (itraconazole, terconazole).31, 32, 34, 90, 111
Small amounts of tioconazole are absorbed systemically when the drug is administered intravaginally.1, 2, 3, 18, 84 In women with vulvovaginal candidiasis, intravaginal application of a single 300-mg dose of tioconazole 6% ointment (not commercially available in the US) resulted in mean peak plasma concentrations of 18 ng/mL (range: 10-35 ng/mL); the time to peak plasma concentrations varied substantially, ranging from 2-24 hours.84 In another study in women with vulvovaginal candidiasis who received a single 300-mg dose of tioconazole as a vaginal suppository (not commercially available in the US), mean plasma concentrations of the drug 8 hours after the dose were 21.2 ng/mL (range: 10.6-35.8 ng/mL); the drug generally was undetectable in plasma 24 hours after the dose.2, 18
While tioconazole generally persists in vaginal fluid for 24-72 hours following intravaginal administration of a single dose of the drug,2, 18, 84, 87 there is considerable interindividual variation in vaginal fluid concentrations.84, 87 In one study in healthy women who received a single 300-mg intravaginal dose of tioconazole as the commercially available 6.5% vaginal ointment, mean vaginal fluid concentrations of the drug 24, 48, and 72 hours after the dose averaged 703, 220, and 91 mcg/mL, respectively.87 In another study in women with vulvovaginal candidiasis who received a single 300-mg dose of tioconazole as a 6% vaginal ointment, mean concentrations of the drug in vaginal fluid were 104, 27, and 15 mcg/mL at 24, 48, and 72 hours, respectively.84 The wide range of tioconazole vaginal fluid concentrations may be related to the dosage form administered, timing of drug administration, and/or the presence or absence of vaginal discharge associated with vulvovaginal candidiasis.87 In most studies, vaginal fluid concentrations of tioconazole following a single 300-mg intravaginal dose remained at concentrations considered sufficient to inhibit the growth of Candida albicans for up to 2-3 days after the dose.2, 18
It is not known whether tioconazole is distributed into human milk.1
Tioconazole does not appear to be metabolized in vaginal fluid, but a portion of the drug that is absorbed systemically following intravaginal application is metabolized.2 Studies in animals and humans indicate that metabolic pathways following systemic absorption are the same regardless of whether the drug is administered orally, intravaginally, or topically to the skin.6, 83 Metabolism of tioconazole involves glucuronidation of the imidazole ring.6, 83 One reported metabolite is formed from N -glucuronidation of a nitrogen on the imidazole ring;2, 6 another is formed by O -dethienylation of a chlorothienyl group, hydration to an alcohol, and glucuronidation.2
Following intravaginal administration of tioconazole, the systemically absorbed fraction of the dose usually is eliminated from plasma within 72 hours.2 Studies using radiolabeled oral tioconazole indicate that approximately 25-27% of the dose is excreted in urine as metabolites and 59% of the dose is excreted in feces (principally as unchanged drug).2, 6
Tioconazole, a synthetic azole antifungal agent, is an imidazole derivative.2, 3, 49, 65 Tioconazole is structurally related to other imidazole-derivative azole antifungals (e.g., butoconazole, clotrimazole, econazole, ketoconazole, miconazole, oxiconazole, sulconazole).2, 3, 49, 65 The drug differs from miconazole in that a chlorothienyl group is substituted in the side chain in place of the dichlorobenzyl group contained in miconazole.2
Tioconazole occurs as a white to off-white, crystalline solid.2 The drug is practically insoluble in water and relatively soluble in alcohol.2
For vaginal use, tioconazole is commercially available as an ointment in a white petrolatum and magnesium aluminum silicate base; butylated hydroxyanisole (BHA) is added as a preservative.1 Each gram of commercially available tioconazole vaginal ointment contains 65 mg of tioconazole.1
Tioconazole vaginal ointment should be stored at 15-30°C.1, 123, 124 The ointment has an expiration date of 3 years following the date of manufacture.91
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 | Ointment | 6.5%* | 1-Day® (available in prefilled, disposable applicators) | Personal Products |
Tioconazole Vaginal Ointment (available in prefilled, disposable applicators) | ||||
Vagistat®-1 (available in prefilled, disposable applicators) | Novartis |
* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
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