Miconazole 1 (miconazole nitrate)

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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.

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Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

Fluconazole; Miconazole/Cisapride

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Inhibition of metabolism of cisapride by azole antifungal agents by CYP3A4.(1)

CLINICAL EFFECTS: Increased serum concentrations of cisapride resulting in possible life-threatening cardiotoxicity, including prolongation of the QT interval.

PREDISPOSING FACTORS: The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(7) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibitors its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(7)

PATIENT MANAGEMENT: Concomitant administration of fluconazole or miconazole with cisapride is contraindicated.

DISCUSSION: Elevated plasma levels of cisapride can cause QT prolongation and torsades de pointes-type ventricular tachycardia which may be fatal. Ketoconazole is contraindicated with concurrent administration of cisapride because ketoconazole has resulted in markedly elevated cisapride serum levels and prolonged QT interval. Serious cardiovascular events, including QT prolongation, torsades de pointes, ventricular tachycardia, cardiac arrest, and/or sudden death have been reported in patients taking cisapride in combination with itraconazole and/or other CYP P-450-3A4 inhibitors.(3) Cisapride is metabolized by CYP3A4. In vitro studies have shown itraconazole, miconazole, posaconazole, and voriconazole to be potent inhibitors of CYP3A4 and like ketoconazole, these agents are also expected to markedly increase cisapride serum concentrations. One or more of the drug pairs linked to this monograph have been included in a list of interactions that should be considered "high-priority" for inclusion and should not be inactivated in EHR systems. This DDI subset was vetted by an expert panel commissioned by the U.S. Office of the National Coordinator (ONC) for Health Information Technology.

Misc Antifungal Agents/Astemizole; Terfenadine

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Fluconazole, itraconazole, ketoconazole, posaconazole, and voriconazole inhibit the metabolism of astemizole and terfenadine.

CLINICAL EFFECTS: Increased serum levels of astemizole and terfenadine with possibly increased side effects including life-threatening cardiac arrhythmias such as QT prolongation or torsades de pointes. Fatalities have been reported from the combination of azole antifungals with astemizole and terfenadine.

PREDISPOSING FACTORS: The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(23) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(22)

PATIENT MANAGEMENT: Until further clinical data are available, because of the potential seriousness of this possible interaction, avoid concomitant administration of these drugs. The concurrent use of terfenadine or astemizole and ketoconazole or itraconazole is contraindicated according to package labeling. The concurrent use of fluconazole at doses of 400 mg per day or greater with terfenadine is contraindicated. Concurrent therapy with fluconazole doses of less than 400 mg per day with terfenadine should be carefully monitored. The manufacturer of voriconazole states that concurrent administration with astemizole or terfenadine is contraindicated. The concurrent use of posaconazole and either astemizole or terfenadine is contraindicated. Fexofenadine, desloratadine, and loratadine, nonsedating antihistamines which have been shown to have no effects on cardiac function, may be alternative in patients receiving azole antifungals. If concurrent therapy is deemed medically necessary, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.

DISCUSSION: Cardiac toxicity (torsades de pointes, a form of polymorphic ventricular tachycardia associated with prolongation of the QT interval) was reported in a 39-year old woman taking terfenadine and ketoconazole concomitantly.(1) Plasma terfenadine levels were higher than expected for a patient receiving 60 mg twice daily. When electrocardiograms from patients receiving terfenadine and ketoconazole concurrently were compared with electrocardiograms from patients receiving only ketoconazole, a 10 to 20 millisecond prolongation in the corrected QT interval was found at times of high, unchanged terfenadine levels and lower than normal levels of the acid metabolite.(3) One study of concurrent therapy with fluconazole 200 mg daily did not show a prolongation of the QTc interval, while another study with fluconazole dosages of 400 mg and 800 mg daily showed significant increases in plasma levels of terfenadine.(13) In a study in 24 healthy subjects, concurrent ketoconazole (400 mg daily) and fexofenadine (120 mg twice daily) increased the fexofenadine maximum concentration (Cmax) and area-under-curve (AUC) by 135% and 164%, respectively. However, there were no changes in adverse effects or QTc interval.(14)

Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

Select Azole Antifungal Agents/Coumarin Anticoagulants

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: The more potent warfarin S-enantiomer is metabolized by CYP2C9 while the weaker R-enantiomer is metabolized by CYP1A2 and CYP3A4. Miconazole is a moderate-strong inhibitor of CYP2C9; fluconazole is a moderate inhibitor of CYP2C9 and CYP3A4; voriconazole and ketoconazole are both weak inhibitors of CYP2C9 and strong inhibitors of CYP3A4.

CLINICAL EFFECTS: Concurrent use of select azole antifungals and coumarin anticoagulants may increase the risk for bleeding.

PREDISPOSING FACTORS: The antifungal dose and inhibitory potency, particularly for CYP2C9, are drug factors which affect the magnitude of this interaction. The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Additional drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs). Azole antifungal inhibition of CYP2C9, may increase the risk of conversion to the CYP2C9 poor metabolizer phenotype. Patients with CYP2C9 intermediate metabolizer genotype are expected to be the most susceptible to this phenoconversion. Patients with a pre-existing CYP2C9 poor metabolizer genotype would be less susceptible to this interaction. However, patients with reduced function genotypes (e.g. CYP2C9 *1/*3, *2/*2, *2/*3, and *3/*3) have an inherently higher risk for bleeding at usual anticoagulant doses and thus generally require lower doses to achieve effective and safe anticoagulation. In addition, CYP2C9 poor metabolizers require more a prolonged time (>2 to 4 weeks) to achieve maximum INR effect for a given dosage regimen than patients without these CYP2C9 variants.

PATIENT MANAGEMENT: In patients receiving warfarin when fluconazole, voriconazole, miconazole or ketoconazole is started, anticipate the need for a dose reduction. Check the baseline INR then closely monitor and adjust the dose of warfarin until the INR has stabilized on the combination. After the azole therapy is discontinued, close monitoring is again needed as the INR may fall after removal of the inhibitor. If concurrent therapy is warranted, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling. The time of highest risk for a coumarin-type drug interaction is when the precipitant drug is initiated or discontinued. Contact the prescriber before initiating, altering the dose or discontinuing either drug.

DISCUSSION: Selected azole antifungal agents can cause an increase in the anticoagulant effects of warfarin. The drug-related risk is dependent on the specific azole, dose and route. A large systematic review was performed on 72 warfarin drug-drug interactions studies that reported on bleeding, thromboembolic events, or death. Most studies were retrospective cohorts. A meta-analysis of 11 of those studies found a higher rate of clinically significant bleeding in patients on warfarin and antimicrobials (OR=1.63; 95% CI 1.45-1.83). Increased bleeding risk was also seen in subgroup analyses with azole antifungals (OR=1.86; 95% CI 1.40-2.47). A retrospective review compared the changes in warfarin effects with coadministration of fluconazole, itraconazole, or voriconazole in 18, 6, and 5 patients, respectively. Mean INR increased from 1.4 to 2.94 in patients taking fluconazole (p<0.001) and increased >20% in 15 out of 18 patients. Mean INR increased from 1.95 to 2.89 in patients taking voriconazole (p<0.05) and increased >20% in 4 out of 5 patients. Mean INR increased slightly from 1.86 to 1.92 in patients taking itraconazole (p=0.37) and did not increase >20% in any patient. In healthy subjects, the administration of voriconazole (300 mg every 12 hours for 12 days) prior to warfarin (30 mg single dose) doubled the prothrombin time when compared to warfarin plus placebo. A large epidemiologic study evaluated the risk for hospitalization due to gastrointestinal (GI) bleeding in warfarin patients treated with or without various anti-infective agents, including fluconazole. Warfarin patients treated with fluconazole had an approximately 2-fold increase in risk for hospitalization due to a GI bleed compared with warfarin patients without infection or warfarin patients receiving alternative anti-infective treatment (e.g. cephalexin, amoxicillin). This risk was highest in patients who received fluconazole 6 to 15 days prior to admission, leading authors to suggest this risk was due to a pharmacokinetic interaction between warfarin and fluconazole, and not due to infection or infection sequelae (e.g. change in diet or gut bacteria). A drug-drug interaction study was performed to evaluate the effect of a single 150 mg dose of fluconazole on prothrombin times in 6 women who had received warfarin therapy for at least 6 months and had stable, therapeutic INRs. Three of 6 women had an INR > 4 or had a bleeding episode: one woman had an INR of 4.6 on day 2, one woman had an INR of 5.2 on day 5, and one woman developed a subconjunctival hemorrhage in the absence of trauma or physical straining on day 6 (INR = 3.4). Miconazole is the most potent known CYP2C9 inhibitor in vivo. In an interaction study in 6 healthy volunteers, oral miconazole 125 mg daily for 18 days increased warfarin exposure (AUC, area-under-curve) 4.7-fold. Black stools have been reported with warfarin and administration of miconazole oral gel. Documentation for oral ketoconazole is less conclusive. However, as ketoconazole is considered a moderate CYP2C9 inhibitor an interaction with warfarin would be expected.

Selected Cyp3a4 Inhibitor/Tolterodine (>1 MG IR OR >2 MG ER)

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Cyclosporine, erythromycin, miconazole, and vinblastine may inhibit the metabolism of tolterodine by CYP3A4.(1,2)

CLINICAL EFFECTS: The concurrent administration of tolterodine with cyclosporine, erythromycin, miconazole, or vinblastine may result in elevated levels of tolterodine and signs of toxicity.(1,2)

PREDISPOSING FACTORS: Patients who are CYP2D6 poor metabolizers may be at increased risk.(1,2) The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(3) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(3) The risk of anticholinergic toxicities including cognitive decline, delirium, falls and fractures is increased in geriatric patients using more than one medicine with anticholinergic properties.(4)

PATIENT MANAGEMENT: The manufacturer of tolterodine recommends that a maximum tolterodine dosage of 1 mg twice daily of the non extended release dosage form(1) or 2 mg once daily of the extended release dosage form(2) be used in patients receiving concurrent therapy with cyclosporine, erythromycin, miconazole, or vinblastine. If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.

DISCUSSION: In a study in eight subjects who were deficient in CYP2D6, the concurrent administration of tolterodine (2 mg) with ketoconazole (200 mg once daily for four days), another inhibitor of CYP3A4, resulted in a 60% decrease in tolterodine clearance.(5) Tolterodine AUC and Cmax increased 2.5-fold and 2-fold, respectively.(2) In a study of the effect of tolterodine immediate release tablets, the effect on the QT interval appeared greater for 8 mg/day (two times the therapeutic dose) compared to 4 mg/day. Tolterodine 2 mg BID and tolterodine 4 mg BID increased the QTcF by 5.01 msec (0.28-9.74 msec) and 11.84 msec (7.11-16.58 msec), respectively. The change in QT interval was more pronounced in CYP2D6 poor metabolizers (PM) than extensive metabolizers (EMs).(1,2)

Moderate Interaction: Assess the risk to the patient and take action as needed.

Selected Cyp3a4 Inhibitors/Tolterodine (<=1 MG OR <=2 MG ER)

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Cyclosporine, erythromycin, miconazole, and vinblastine may inhibit the metabolism of tolterodine by CYP3A4.(1,2)

CLINICAL EFFECTS: The concurrent administration of tolterodine with cyclosporine, erythromycin, miconazole, or vinblastine may result in elevated levels of tolterodine and signs of toxicity.(1,2)

PREDISPOSING FACTORS: Patients who are CYP2D6 poor metabolizers may be at increased risk.(1,2) The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(3) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(3) The risk of anticholinergic toxicities including cognitive decline, delirium, falls and fractures is increased in geriatric patients using more than one medicine with anticholinergic properties.(4)

PATIENT MANAGEMENT: The manufacturer of tolterodine recommends that a maximum tolterodine dosage of 1 mg twice daily of the non extended release dosage form(1) or 2 mg once daily of the extended release dosage form(2) be used in patients receiving concurrent therapy with cyclosporine, erythromycin, miconazole, or vinblastine. If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.

DISCUSSION: In a study in eight subjects who were deficient in CYP2D6, the concurrent administration of tolterodine (2 mg) with ketoconazole (200 mg once daily for four days), another inhibitor of CYP3A4, resulted in a 60% decrease in tolterodine clearance.(5) Tolterodine AUC and Cmax increased 2.5-fold and 2-fold, respectively.(2) In a study of the effect of tolterodine immediate release tablets, the effect on the QT interval appeared greater for 8 mg/day (two times the therapeutic dose) compared to 4 mg/day. Tolterodine 2 mg BID and tolterodine 4 mg BID increased the QTcF by 5.01 msec (0.28-9.74 msec) and 11.84 msec (7.11-16.58 msec), respectively. The change in QT interval was more pronounced in CYP2D6 poor metabolizers (PM) than extensive metabolizers (EMs).(1,2)

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There are no contraindication contraindications for this drug.

There are no severe contraindications for this drug.

• No disease contraindications

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Rare or Very Rare

• Abnormal vaginal bleeding
• Anaphylaxis
• Angioedema
• Bronchospastic pulmonary disease
• Dyspnea
• Toxic epidermal necrolysis
• Urticaria

Less Frequent

• Dysmenorrhea
• Fever
• Genital organ pruritus
• Vaginal discharge

Rare or Very Rare

• Acute abdominal pain
• Chills
• Contact dermatitis
• Cystitis
• Dizziness
• Facial edema
• Flu-like symptoms
• General weakness
• Headache disorder
• Nausea
• Pruritus of skin
• Skin rash
• Vaginal burning
• Vaginal irritation
• Vaginitis
• Vulvovaginal pain

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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.

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

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