ATC Class:D01AC02

VA Class:DE102

AHFS Class:

• Azoles 84:04.08.08

Generic Name(s):

• Miconazole Nitrate

Miconazole nitrate, an imidazole derivative, a synthetic azole antifungal agents.

Dermatophytoses and Cutaneous Candidiasis

Miconazole nitrate is used topically for the treatment of tinea pedis, tinea cruris, and tinea corporis caused by T. mentagrophytes, T. rubrum , or Epidermophyton floccosum and for the treatment of cutaneous candidiasis (moniliasis). Like other imidazole derivatives (e.g., clotrimazole, econazole, ketoconazole, oxiconazole, sulconazole) and ciclopirox olamine, miconazole nitrate has an advantage over some other topical antifungal agents (e.g., nystatin, tolnaftate) in that it is active against both dermatophytes and Candida .

Tinea corporis and tinea cruris generally can be effectively treated using a topical antifungal; however, an oral antifungal may be necessary if the disease is extensive, dermatophyte folliculitis is present, the infection is chronic or does not respond to topical therapy, or the patient is immunocompromised because of coexisting disease or concomitant therapy.104,105,106,108 Many clinicians consider topical imidazole-derivative azole antifungals (e.g., clotrimazole, econazole, ketoconazole, miconazole, oxiconazole, sulconazole) or topical allylamine antifungals (e.g., naftifine, terbinafine) the drugs of first choice for the topical treatment of tinea corporis or tinea cruris,105,109 although other antifungal agents (e.g., ciclopirox olamine, butenafine hydrochloride, tolnaftate, undecylenic acid) also can be effective in the treatment of these infections.104,105,106,107,108 While topical antifungals usually are effective for the treatment of uncomplicated tinea manuum and tinea pedis,104,105,106,107,108 an oral antifungal usually is necessary for the treatment of hyperkeratotic areas on the palms and soles,105,108 for chronic moccasin-type (dry-type) tinea pedis,104,105,107 and for the treatment of tinea unguium (onychomycosis).104,105,106,107,108

Pityriasis (Tinea) Versicolor

Miconazole nitrate is used topically for the treatment of pityriasis (tinea) versicolor caused by Malassezia furfur ( Pityrosporum orbiculare or P. ovale ). 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%).104,105,107,110,111,112 However, an oral antifungal (e.g., itraconazole, ketoconazole) may be indicated, with or without a topical agent, in patients who have extensive or severe infections or who fail to respond to or have frequent relapses with topical therapy.107,110,111

Vulvovaginal Candidiasis

Uncomplicated Vulvovaginal Candidiasis

Miconazole nitrate is used intravaginally for the treatment of vulvovaginal candidiasis.100,102,135 Prior to initial use of miconazole 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;100,102 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.100 Miconazole vaginal cream or vaginal suppositories may be used for self-medication of vulvovaginal candidiasis in otherwise healthy, nonpregnant women who have been previously diagnosed by a clinician and are having a recurrence of similar symptoms.100 When an adequate response is not achieved following a course of miconazole 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 identify unusual Candida species (e.g., C. glabrata) .100

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,100,114,115 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).100,114,118 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),100,114,115,117,118 these factors are not present in most women who have recurrent episodes.100,102,119

Azole antifungals (imidazole and triazole derivatives) are considered the drugs of choice for the treatment of vulvovaginal candidiasis.100,102,113,114,115,118,119,135 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 , or 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.100,113,114,115,118,119,135 These regimens generally have been associated with clinical and mycologic cure rates of 80-90% in otherwise healthy, nonpregnant women with uncomplicated infections,100,114,115,118,119 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.114,115,119 While intravaginal nystatin also can be used for the treatment of uncomplicated vulvovaginal candidiasis, it generally is less effective than intravaginal azole antifungals.100,135 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.100,102,114,115,118,123 Complicated vulvovaginal candidiasis is defined as infections that are recurrent or severe, caused by Candida other than C. albicans , or occurring in pregnant women or women with underlying disease such as uncontrolled diabetes, debilitation, or immunosuppression.100 (See Complicated and Recurrent Vulvovaginal Candidiasis under Uses: Vulvovaginal Candidiasis.)

Cure rates of 80-95% have been reported in patients receiving once-daily intravaginal application of miconazole nitrate for a 2-week period. Randomized clinical trials using miconazole nitrate cream or suppositories have shown that treatment regimens of 7 days or longer have cure rates equivalent to 14-day regimens. Clinical studies comparing a 7-day treatment regimen using the vaginal cream with a 3-day treatment regimen using the 200-mg vaginal suppositories have shown that the cure rate with the suppository regimen was slightly lower, but not statistically different from, that with the cream regimen. A 7-day treatment regimen using the vaginal cream has been shown to be effective for the treatment of vulvovaginal candidiasis during pregnancy, but the manufacturer states that the efficacy of the vaginal suppositories for the treatment of this infection during pregnancy has not been established. The efficacy of a 3-day treatment regimen using the 200-mg vaginal suppositories in diabetic patients has not been established. In 2 comparative studies, 2% miconazole nitrate cream applied intravaginally once daily for 2 weeks resulted in greater cure rates for vulvovaginal candidiasis than did 100,000 units of nystatin inserted intravaginally as tablets once or twice daily for 2 weeks.

Vulvovaginal candidiasis usually is not acquired through sexual activity,100,116,124 and treatment of sexual partner(s) is not recommended but may be considered in women who have recurrent infections.100,116,124 However, male sexual partners who have symptomatic balanitis or penile dermatitis may benefit from treatment with a topical antifungal agent to relieve symptoms.100

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 each year) have not been established.100,114,115,117,118,119 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.100 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).100 For the maintenance regimen, the CDC recommends oral fluconazole (100-, 150-, or 200-mg doses once weekly).100 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.100 These maintenance regimens can be effective in reducing recurrent infections; however, 30-50% of women will have recurrent disease once maintenance therapy is discontinued.100

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.100 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 or those receiving corticosteroid therapy).100

For the treatment of vulvovaginal candidiasis during pregnancy, the CDC recommends use of a 7-day regimen of an intravaginal azole antifungal.100

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.103,119 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.100,119 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.100,119,124

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 ).117,118,119,120,121,122,123 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.118,119,120,121,122,123 Optimum therapy for the treatment of vulvovaginal candidiasis caused by Candida with reduced susceptibility to azole antifungals has not been determined to date.119 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.100 Referral to a specialist is advised.100

Administration

Miconazole nitrate is administered topically as a cream, powder, or aerosol powder or tincture, or intravaginally as a vaginal cream or suppository. Miconazole powder or aerosol powder are not recommended for use on the scalp or nails.

Dosage

Dermatophytoses and Cutaneous Candidiasis

For the treatment of tinea pedis, tinea cruris, or tinea corporis, topical miconazole nitrate preparations are applied sparingly to the cleansed, dry infected area twice daily in the morning and evening, or as directed by a physician. When used for the treatment of tinea pedis, special attention during application should be paid to the spaces between the toes. It also is helpful to wear well-fitting, ventilated shoes and to change shoes and socks at least once daily. For the treatment of cutaneous candidiasis, miconazole nitrate cream is applied twice daily.

Symptomatic improvement may occur within several days to 1 week, and clinical improvement may be evident by the second week of therapy. Cutaneous candidiasis and tinea cruris and corporis should be treated for 2 weeks and tinea pedis for 1 month to reduce the possibility of recurrence. If clinical improvement does not occur after 1 month of treatment, the diagnosis should be reevaluated. When miconazole nitrate is used for self-medication , tinea cruris should usually be treated for 2 weeks and tinea pedis or corporis for 4 weeks; if adequate results have not been obtained after these treatment periods, the drug should be discontinued and a physician or pharmacist consulted.

Pityriasis (Tinea) Versicolor

For the treatment of pityriasis (tinea) versicolor, miconazole nitrate cream is applied once daily. Clinical and mycologic clearing usually occur after 2 weeks of treatment.

Vulvovaginal Candidiasis

For the treatment of vulvovaginal candidiasis, one 200-mg suppository is administered intravaginally once daily at bedtime for 3 consecutive days or 100 mg of miconazole nitrate (one 100-mg suppository or 5 g of the 2% cream) is administered intravaginally once daily at bedtime for 7 days.100 The 7-day regimen is preferred in pregnant patients with vulvovaginal candidiasis.100,102 For the management of external vulvar itching and irritation associated with vulvovaginal candidiasis, a sufficient amount of miconazole nitrate 2% external vulvar cream should be applied to affected areas twice daily (morning and evening) for up to 7 days as needed. A course of therapy may be repeated if it has been determined by appropriate smears and cultures that the infecting organism is still miconazole-susceptible Candida .

When miconazole nitrate vaginal suppositories are used for self-medication in the treatment of vulvovaginal candidiasis, one vaginal suppository containing 100 or 200 mg of the drug may be inserted intravaginally once daily (preferably at bedtime) for 7 or 3 consecutive days, respectively. Alternatively, a single-dose regimen using a 1200-mg vaginal suppository may be used. When the 2% vaginal cream is used for self-medication in the treatment of vulvovaginal candidiasis, one applicatorful of the vaginal cream may be inserted intravaginally once daily (preferably at bedtime) for 7 days. If vulvovaginal candidiasis does not improve within 3 days or if the condition persists beyond 7 days, self-medication should be discontinued and the patient should consult a physician.

Adverse Effects

Irritation and burning have occasionally followed cutaneous application of miconazole nitrate cream. To avoid maceration, especially in intertriginous areas, the cream should be used sparingly. If a sensitivity reaction or chemical irritation occurs, application of the cream or lotion should be discontinued.

Miconazole nitrate cream and suppositories for intravaginal administration have caused vulvovaginal burning, itching, or irritation in a small percentage of patients. Pelvic cramps, vaginal burning, headache, hives, and skin rash have occurred rarely. The drug should be discontinued if irritation or hypersensitivity reactions develop.

Contact dermatitis has been reported following topical application of imidazole-derivative azole antifungals (e.g., clotrimazole, econazole, miconazole, oxiconazole, sulconazole, tioconazole).125,126,127,128,129,130 Cross-sensitization appears to occur among the imidazole derivatives; however, cross-sensitivity appears to be unpredictable.125,126,127,128,129,130 The fact that patients with contact sensitivity to one imidazole-derivative azole antifungal may be sensitive to other similar drugs should be considered.126,127,128,129

Precautions and Contraindications

If irritation occurs, or if the patient's skin disease does not improve within 2 weeks for tinea cruris or within 4 weeks for tinea pedis or corporis during self-medication with miconazole, treatment should be discontinued and the patient should consult a physician or pharmacist.

If vulvovaginal candidiasis does not improve within 3 days or if the condition persists beyond 7 days during self-medication with miconazole nitrate vaginal suppositories or cream, the patient should consult a physician, as a condition other than vulvovaginal candidiasis may exist. If symptoms of vulvovaginal candidiasis recur within 2 months of using miconazole nitrate vaginal suppositories or cream for self-medication , the patient should consult a physician. Vaginal tampons should not be used in patients receiving miconazole nitrate vaginal suppositories or cream; sanitary napkins may be used instead.

The hydrogenated vegetable oil base contained in miconazole nitrate vaginal suppositories may interact with certain latex products such as vaginal contraceptive diaphragms, and concurrent use is not recommended; in such situations, use of the vaginal cream may be considered as an alternative to the suppositories.

Increased prothrombin time, international normalized ratio (INR), and/or bleeding or bruising have been reported in some patients receiving intravaginal miconazole concomitantly with a coumarin anticoagulant (e.g., warfarin, acenocoumarol).132,133,134 Although the precise mechanism of this interaction is not known, it has been suggested that miconazole can inhibit metabolism of warfarin via inhibition of the cytochrome P-450 (CYP) 2C9 microsomal enzyme system, resulting in increased blood concentrations of warfarin.133,134 Patients already receiving warfarin should be advised not to undertake self-medication with miconazole nitrate vaginal cream or suppositories without first consulting a clinician.132,133,134

Patients who are considering use of miconazole nitrate vaginal cream or suppositories for self-medication should be advised not to use the drug if they have abdominal pain, fever, or malodorous vaginal discharge, as a condition more serious than vulvovaginal candidiasis may exist; such patients should consult a physician immediately. Patients who are considering use of miconazole nitrate vaginal cream or suppositories for self-medication also should be advised not to use the drug if vaginal pruritus or discomfort is occurring for the first time; such patients should consult their physician.

Miconazole nitrate preparations should not come in contact with the eyes. Miconazole nitrate preparations are contraindicated in patients with known hypersensitivity to the drug or any ingredient in the formulation.

Pediatric Precautions

Topical miconazole nitrate preparations should be used in children younger than 2 years of age only under the direction and supervision of a physician. Use of the topical preparations in children 2-11 years of age should be supervised by an adult. For self-medication , miconazole nitrate vaginal suppositories or cream should not be used in children younger than 12 years of age.

Carcinogenicity

Long-term animal studies to determine the carcinogenic potential of miconazole nitrate have not been performed.

Pregnancy and Lactation

Pregnancy

Because small amounts of miconazole nitrate are absorbed from the vagina, the manufacturer states that the vaginal preparations should not be used in the first trimester of pregnancy unless the drug is considered essential to the welfare of the patient. For self-medication , miconazole nitrate vaginal suppositories or vaginal cream should not be used in pregnant women unless otherwise instructed by a physician. Follow-up reports from clinical studies during which miconazole vaginal preparations were used for up to 14 days in pregnant women have revealed no adverse effects or complications attributable to therapy with the drug in infants born to these women. Prolonged gestation has occurred in rats, but not in rabbits, receiving oral miconazole nitrate. In addition, fetotoxicity and embryotoxicity have occurred in rats and rabbits and dystocia in rats in reproduction studies using oral miconazole nitrate dosages of 80 mg/kg and higher; these effects were not observed in rats following intravaginal administration of the drug.

Lactation

It is not known whether miconazole nitrate is distributed into milk. Miconazole nitrate should be used with caution in nursing women.

Mechanism of Action

Miconazole nitrate exerts its antifungal and antibacterial activity by altering cell membrane permeability; its site of action on cell membranes has not been elucidated. As a result of this alteration of permeability, the cell membrane is unable to function as a selective barrier, and potassium and other cellular constituents are lost.

Spectrum

Miconazole nitrate inhibits several genera of fungi, including dermatophytes and yeasts, and gram-positive bacteria. In vitro, concentrations of 1 mcg/mL or less inhibit Candida albicans, Epidermophyton floccosum, Trichophyton mentagrophytes, T. rubrum, Microsporum canis , and Staphylococcus aureus . Miconazole concentrations of 10 mcg/mL are required to inhibit C. guilliermondi and C. tropicalis . Higher drug concentrations are necessary for fungicidal activity.

Pharmacokinetics

Absorption

There have been no reports to date indicating that miconazole nitrate is absorbed following topical application to intact skin.

Small amounts of miconazole are absorbed systemically when the drug is administered intravaginally. Average peak serum concentrations of 4.2 ng/mL have been reported after 6 daily applications of a 14-day regimen for treatment of vulvovaginal candidiasis; serum concentrations did not increase further during the remainder of the treatment period. Following intravaginal administration of a single dose of miconazole (cream or suppository) to healthy women, about 1% of the dose is recovered in urine and feces.

Chemistry and Stability

Chemistry

Miconazole nitrate, an imidazole derivative, is a synthetic azole antifungal agent. Miconazole is structurally related to other imidazole-derivative azole antifungal agents (e.g., butoconazole, clotrimazole, econazole, ketoconazole, oxiconazole, sulconazole, tioconazole). Miconazole nitrate occurs as a white microcrystalline powder and is very slightly soluble in water and slightly soluble in alcohol.

Stability

Miconazole nitrate topical and vaginal preparations should be stored in tight containers at 15-30°C.

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