Miconazole Nitrate

DRUG IMAGES

MICONAZOLE 2% TOPICAL CREAM
MICONAZOLE 2% VAGINAL CREAM

The following indications for MICONAZOLE NITRATE (miconazole nitrate) have been approved by the FDA:

Indications:
Cutaneous candidiasis
Tinea corporis
Tinea cruris
Tinea pedis
Tinea versicolor
Vulvovaginal candidiasis

Professional Synonyms:
Corporeal ringworm
Cutaneous candidosis
Cutaneous moniliasis
Dermatomycosis pedis
Dhobie itch
Eczema marginatum
Jock itch
Pityriasis versicolor
Tinea circinata
Tinea furfuracea
Tinea glabrosa
Tinea inguinalis
Tinea of the foot
Vaginal candidiasis
Vulvovaginal candidosis
Vulvovaginal moniliasis

The following dosing information is available for MICONAZOLE NITRATE (miconazole nitrate):

Dosing
Administration
MICONAZOLE NITRATE
MICONAZOLE 7

No enhanced Dosing information available for this drug.

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.

Dosing information for MICONAZOLE NITRATE
DRUG LABEL	DOSING TYPE	DOSING INSTRUCTIONS
MICONAZOLE 2% TOPICAL CREAM	Maintenance	Adults apply to the affected area(s) by topical route 2 times per day in the morning and evening
MICONAZOLE 2% VAGINAL CREAM	Maintenance	Adults insert 1 applicatorful by vaginal route once daily at bedtime

Generic dosing information for MICONAZOLE 7
DRUG LABEL	DOSING TYPE	DOSING INSTRUCTIONS
GS MICONAZOLE 7 CREAM	Maintenance	Adults insert 1 applicatorful by vaginal route once daily at bedtime
MICONAZOLE 2% TOPICAL CREAM	Maintenance	Adults apply to the affected area(s) by topical route 2 times per day in themorning and evening
MICONAZOLE 7 CREAM	Maintenance	Adults insert 1 applicatorful by vaginal route once daily at bedtime
SM MICONAZOLE 7 CREAM	Maintenance	Adults insert 1 applicatorful by vaginal route once daily at bedtime
SM MICONAZOLE 2% VAGINAL CREAM	Maintenance	Adults insert 1 applicatorful by vaginal route once daily at bedtime
SM MICONAZOLE 2% TOPICAL CREAM	Maintenance	Adults apply to the affected area(s) by topical route 2 times per day in themorning and evening
RA MICONAZOLE 7 CREAM	Maintenance	Adults insert 1 applicatorful by vaginal route once daily at bedtime
KRO MICONAZOLE 7 CREAM	Maintenance	Adults insert 1 applicatorful by vaginal route once daily at bedtime
EQ MICONAZOLE 2% VAGINAL CREAM	Maintenance	Adults insert 1 applicatorful by vaginal route once daily at bedtime
EQ MICONAZOLE 7 CREAM	Maintenance	Adults insert 1 applicatorful by vaginal route once daily at bedtime
CVS MICONAZOLE 7 CREAM	Maintenance	Adults insert 1 applicatorful by vaginal route once daily at bedtime
MICONAZOLE 2% VAGINAL CREAM	Maintenance	Adults insert 1 applicatorful by vaginal route once daily at bedtime
QC MICONAZOLE-7 CREAM	Maintenance	Adults insert 1 applicatorful by vaginal route once daily at bedtime
MICONAZOLE-7 CREAM	Maintenance	Adults insert 1 applicatorful by vaginal route once daily at bedtime
FT MICONAZOLE 7 CREAM	Maintenance	Adults insert 1 applicatorful by vaginal route once daily at bedtime
QC MICONAZOLE 7 CREAM	Maintenance	Adults insert 1 applicatorful by vaginal route once daily at bedtime
GNP MICONAZOLE 7 CREAM	Maintenance	Adults insert 1 applicatorful by vaginal route once daily at bedtime

The following drug interaction information is available for MICONAZOLE NITRATE (miconazole nitrate):

Contraindicated
Severe
Moderate

There are 0 contraindications.

There are 2 severe interactions. These drug interactions can produce serious consequences in most patients. Actions required for severe interactions include, but are not limited to, discontinuing one or both agents, adjusting dosage, altering administration scheduling, and providing additional patient monitoring. Review the full interaction monograph for more information.

Drug Interaction	Drug Names
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.	ANISINDIONE, DICUMAROL, JANTOVEN, WARFARIN SODIUM
Tolterodine (Greater Than 1 mg IR or Greater Than 2 mg ER)/Selected CYP3A4 Inhibitors 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)	TOLTERODINE TARTRATE, TOLTERODINE TARTRATE ER

Drug Interaction

Drug Names

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.

ANISINDIONE, DICUMAROL, JANTOVEN, WARFARIN SODIUM

Tolterodine (Greater Than 1 mg IR or Greater Than 2 mg ER)/Selected CYP3A4 Inhibitors

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)

TOLTERODINE TARTRATE, TOLTERODINE TARTRATE ER

There are 2 moderate interactions. The clinician should assess the patient’s characteristics and take action as needed. Actions required for moderate interactions include, but are not limited to, discontinuing one or both agents, adjusting dosage, altering administration.

Drug Interaction	Drug Names
Azole Antifungals/Sulfonylureas SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Azole antifungals inhibit the metabolism of sulfonylureas. CLINICAL EFFECTS: Increased effectiveness of the sulfonylurea which may result in clinical symptoms of hypoglycemia. PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Monitor blood glucose levels during concurrent therapy. The dose of the sulfonylurea may need to be adjusted. DISCUSSION: Prospective and retrospective studies in healthy subjects have documented an interaction between the sulfonylureas and fluconazole, ketoconazole, and miconazole. In vitro studies have shown the metabolism of sulfonylureas to be inhibited by ketoconazole, clotrimazole, and miconazole. In 13 healthy males, fluconazole increased the maximum concentration (Cmax) and area-under-curve (AUC) of a single dose of glipizide (2.5 mg) by 19% and 49%, respectively. In 20 healthy males, fluconazole increased the Cmax and AUC of a single dose of glyburide (5 mg) by 19% and 44%, respectively. In 13 healthy males, fluconazole increased the Cmax and AUC of a single dose of tolbutamide (500 mg) by 11% and 26%, respectively. Although itraconazole was found to have no effect on tolbutamide clearance in a study in rats, additional information is needed to determine if an interaction occurs. In healthy subjects, glucose concentrations decreased during concurrent therapy with glipizide and posaconazole. Voriconazole has been shown to inhibit CYP2C9.	DUETACT, GLIMEPIRIDE, GLIPIZIDE, GLIPIZIDE ER, GLIPIZIDE XL, GLIPIZIDE-METFORMIN, GLUCOTROL XL, GLYBURIDE, GLYBURIDE MICRONIZED, GLYBURIDE-METFORMIN HCL, PIOGLITAZONE-GLIMEPIRIDE
Tolterodine (Less Than or Equal To 1 mg or Less Than or Equal To 2 mg ER)/Selected CYP3A4 Inhibitors 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)	TOLTERODINE TARTRATE, TOLTERODINE TARTRATE ER

Drug Interaction

Drug Names

Azole Antifungals/Sulfonylureas

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

MECHANISM OF ACTION: Azole antifungals inhibit the metabolism of sulfonylureas.

CLINICAL EFFECTS: Increased effectiveness of the sulfonylurea which may result in clinical symptoms of hypoglycemia.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Monitor blood glucose levels during concurrent therapy. The dose of the sulfonylurea may need to be adjusted.

DISCUSSION: Prospective and retrospective studies in healthy subjects have documented an interaction between the sulfonylureas and fluconazole, ketoconazole, and miconazole. In vitro studies have shown the metabolism of sulfonylureas to be inhibited by ketoconazole, clotrimazole, and miconazole. In 13 healthy males, fluconazole increased the maximum concentration (Cmax) and area-under-curve (AUC) of a single dose of glipizide (2.5 mg) by 19% and 49%, respectively.

In 20 healthy males, fluconazole increased the Cmax and AUC of a single dose of glyburide (5 mg) by 19% and 44%, respectively. In 13 healthy males, fluconazole increased the Cmax and AUC of a single dose of tolbutamide (500 mg) by 11% and 26%, respectively. Although itraconazole was found to have no effect on tolbutamide clearance in a study in rats, additional information is needed to determine if an interaction occurs.

In healthy subjects, glucose concentrations decreased during concurrent therapy with glipizide and posaconazole. Voriconazole has been shown to inhibit CYP2C9.

DUETACT, GLIMEPIRIDE, GLIPIZIDE, GLIPIZIDE ER, GLIPIZIDE XL, GLIPIZIDE-METFORMIN, GLUCOTROL XL, GLYBURIDE, GLYBURIDE MICRONIZED, GLYBURIDE-METFORMIN HCL, PIOGLITAZONE-GLIMEPIRIDE

Tolterodine (Less Than or Equal To 1 mg or Less Than or Equal To 2 mg ER)/Selected CYP3A4 Inhibitors

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)

TOLTERODINE TARTRATE, TOLTERODINE TARTRATE ER

Moderate List
No disease contraindications

The following adverse reaction information is available for MICONAZOLE NITRATE (miconazole nitrate):

Overview
Severe
Less Severe

Adverse reaction overview.

No enhanced Common Adverse Effects information available for this drug.

There are 9 severe adverse reactions.

More Frequent	Less Frequent
None.	None.

Rare/Very Rare
Abnormal vaginal bleeding Anaphylaxis Angioedema Blistering skin Bronchospastic pulmonary disease Dyspnea Skin rash Toxic epidermal necrolysis Urticaria

There are 24 less severe adverse reactions.

More Frequent	Less Frequent
None.	Dysmenorrhea Fever Genital organ pruritus Vaginal discharge

Rare/Very Rare
Acute abdominal pain Chills Contact dermatitis Cystitis Dermatitis due to topical drug Dizziness Erythema Facial edema Flu-like symptoms General weakness Headache disorder Nausea Paresthesia Pruritus of skin Skin irritation Skin rash Vaginal burning Vaginal irritation Vaginitis Vulvovaginal pain

The following precautions are available for MICONAZOLE NITRATE (miconazole nitrate):

Pediatric
Pregnant
Lactation
Geriatric

No enhanced Pediatric Use information available for this drug.

Contraindicated

None

Severe Precaution

None

Management or Monitoring Precaution

None

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.

No enhanced Geriatric Use information available for this drug.

The following icd codes are available for MICONAZOLE NITRATE (miconazole nitrate)'s list of indications:

Cutaneous candidiasis
B37.2	Candidiasis of skin and nail
Tinea corporis
B35.4	Tinea corporis
Tinea cruris
B35.6	Tinea cruris
Tinea pedis
B35.3	Tinea pedis
Tinea versicolor
B36.0	Pityriasis versicolor
Vulvovaginal candidiasis
B37.3	Candidiasis of vulva and vagina
B37.31	Acute candidiasis of vulva and vagina
B37.32	Chronic candidiasis of vulva and vagina