ITRACONAZOLE CAPSULES, 100 mg

ITRACONAZOLE - itraconazole capsule 
Sandoz Inc

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ITRACONAZOLE CAPSULES, 100 mg

Congestive Heart Failure

Itraconazole Capsules should not be administered for the treatment of onychomycosis in patients with evidence of ventricular dysfunction such as congestive heart failure (CHF) or a history of CHF. If signs or symptoms of congestive heart failure occur during administration of itraconazole capsules, discontinue administration. When itraconazole was administered intravenously to dogs and healthy human volunteers, negative inotropic effects were seen. (See CLINICAL PHARMACOLOGY, Special Populations; CONTRAINDICATIONS; WARNINGS; PRECAUTIONS, Drug Interactionsand ADVERSE REACTIONS, Post-Marketing Experience for more information.)

Drug Interactions: Co-administration of cisapride, pimozide, quinidine, dofetilide or levacetylmethadol (levomethadyl) with itraconazole capsules, injection or oral solution is contraindicated. Itraconazole, a potent cytochrome P450 3A4 isoenzyme system (CYP3A4) inhibitor, may increase plasma concentrations of drugs metabolized by this pathway. Serious cardiovascular events, including QT prolongation, torsades de pointes, ventricular tachycardia, cardiac arrest and/or sudden death have occurred in patients using cisapride, pimozide, levacetylmethadol (levomethadyl) or quinidine concomitantly with itraconazole and/or other CYP3A4 inhibitors.  See CONTRAINDICATIONS; WARNINGS and PRECAUTIONS, Drug Interactions for more information.

DESCRIPTION

Itraconazole is a synthetic triazole antifungal agent. Itraconazole is a 1:1:1:1 racemic mixture of four diastereomers (two enantiomeric pairs), each possessing three chiral centers. It may be represented by the following structural formula and nomenclature:

Chemical Structure

(±)-1-[(R*)-sec-butyl]-4-[p-[4-[p-[[(2R*,4S*)-2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1-piperazinyl]phenyl]-Δ2-1,2,4-triazolin-5-one mixture with (±)-1-[(R*)-sec-butyl]-4-[p-[4-[p-[[(2S*,4R*)-2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1-piperazinyl]phenyl]-Δ2-1,2,4-triazolin-5-one

or

(±)-1-[(RS)-sec-butyl]-4-[p-[4-[p-[[(2R,4S)-2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1-piperazinyl]phenyl]-Δ2-1,2,4-triazolin-5-one.

Itraconazole has a molecular formula of C35H38Cl2N8O4 and a molecular weight of 705.64. It is a white to slightly yellowish powder. It is insoluble in water, very slightly soluble in alcohols and freely soluble in dichloromethane. It has a pKa of 3.7 (based on extrapolation of values obtained from methanolic solutions) and a log (n-octanol/water) partition coefficient of 5.66 at pH 8.1.

Each capsule, for oral administration, contains 100 mg of itraconazole. In addition, each capsule contains the following inactive ingredients: corn starch, hypromellose, polyethylene glycol (PEG) 20,000 and sugar spheres. The capsule shell contains: D&C yellow #10 aluminum lake, FD&C blue #1, FD&C blue #2, FD&C red #40, gelatin, iron oxide black, pharmaceutical glaze, propylene glycol and titanium dioxide.

CLINICAL PHARMACOLOGY

Pharmacokinetics and Metabolism

NOTE: The plasma concentrations reported below were measured by high-performance liquid chromatography (HPLC) specific for itraconazole. When itraconazole in plasma is measured by a bioassay, values reported are approximately 3.3 times higher than those obtained by HPLC due to the presence of the bioactive metabolite, hydroxyitraconazole. (See MICROBIOLOGY.)

The pharmacokinetics of itraconazole after intravenous administration and its absolute oral bioavailability from an oral solution were studied in a randomized crossover study in 6 healthy male volunteers. The observed absolute oral bioavailability of itraconazole was 55%.

The oral bioavailability of itraconazole is maximal when itraconazole capsules are taken with a full meal. The pharmacokinetics of itraconazole were studied in 6 healthy male volunteers who received, in a crossover design, single 100 mg doses of itraconazole as a polyethylene glycol capsule, with or without a full meal. The same 6 volunteers also received 50 mg or 200 mg with a full meal in a crossover design. In this study, only itraconazole plasma concentrations were measured. The respective pharmacokinetic parameters for itraconazole are presented in the table below:

*
mean ± standard deviation
50 mg
(fed)
100 mg
(fed)
100 mg
(fasted)
200 mg
(fed)
Cmax (ng/mL)45 ± 16*132 ± 6738 ± 20289 ± 100
Tmax (hours)3.2 ± 1.34.0 ± 1.13.3 ± 1.04.7 ± 1.4
AUC0-∞ (ng•h/mL)567 ± 2641899 ± 838722 ± 2895211 ± 2116

Doubling the itraconazole dose results in approximately a three-fold increase in the itraconazole plasma concentrations.

Values given in the table below represent data from a crossover pharmacokinetics study in which 27 healthy male volunteers each took a single 200 mg dose of itraconazole capsules with or without a full meal:

*
mean ± standard deviation
ItraconazoleHydroxyitraconazole
FedFastedFedFasted
Cmax (ng/mL)239 ± 85*140 ± 65397 ± 103286 ± 101
Tmax (hours)4.5 ± 1.13.9 ± 1.05.1 ± 1.64.5 ± 1.1
AUC0-∞ (ng•h/mL)3423 ± 11542094 ± 9057978 ± 26485191 ± 2489
t1/2 (hours)21 ± 521 ± 712 ± 312 ± 3

Absorption of itraconazole under fasted conditions in individuals with relative or absolute achlorhydria, such as patients with AIDS or volunteers taking gastric acid secretion suppressors (e.g., H2 receptor antagonists), was increased when itraconazole capsules were administered with a cola beverage. Eighteen men with AIDS received single 200 mg doses of itraconazole capsules under fasted conditions with 8 ounces of water or 8 ounces of a cola beverage in a crossover design. The absorption of itraconazole was increased when itraconazole capsules were co-administered with a cola beverage, with AUC0-24 and Cmax increasing 75% ± 121% and 95% ± 128%, respectively.

Thirty healthy men received single 200 mg doses of itraconazole capsules under fasted conditions either 1) with water; 2) with water, after ranitidine 150 mg b.i.d. for 3 days; or 3) with cola, after ranitidine 150 mg b.i.d. for 3 days. When itraconazole capsules were administered after ranitidine pretreatment, itraconazole was absorbed to a lesser extent than when itraconazole capsules were administered alone, with decreases in AUC0-24 and Cmax of 39% ± 37% and 42% ± 39%, respectively. When itraconazole capsules were administered with cola after ranitidine pretreatment, itraconazole absorption was comparable to that observed when itraconazole capsules were administered alone. (See PRECAUTIONS, Drug Interactions.)

Steady-state concentrations were reached within 15 days following oral doses of 50 mg to 400 mg daily. Values given in the table below are data at steady-state from a pharmacokinetics study in which 27 healthy male volunteers took 200 mg itraconazole capsules b.i.d. (with a full meal) for 15 days:

*
mean ± standard deviation
ItraconazoleHydroxyitraconazole
Cmax (ng/mL)2282 ± 514*3488 ± 742
Cmin (ng/mL)1855 ± 5353349 ± 761
Tmax (hours)4.6 ± 1.83.4 ± 3.4
AUC0-12 h (ng•h/mL)22569 ± 537538572 ± 8450
t1/2 (hours)64 ± 3256 ± 24

The plasma protein binding of itraconazole is 99.8% and that of hydroxyitraconazole is 99.5%. Following intravenous administration, the volume of distribution of itraconazole averaged 796 ± 185 liters.

Itraconazole is metabolized predominantly by the cytochrome P450 3A4 isoenzyme system (CYP3A4), resulting in the formation of several metabolites, including hydroxyitraconazole, the major metabolite. Results of a pharmacokinetics study suggest that itraconazole may undergo saturable metabolism with multiple dosing. Fecal excretion of the parent drug varies between 3% to 18% of the dose. Renal excretion of the parent drug is less than 0.03% of the dose. About 40% of the dose is excreted as inactive metabolites in the urine. No single excreted metabolite represents more than 5% of a dose. Itraconazole total plasma clearance averaged 381 ± 95 mL/minute following intravenous administration. (See CONTRAINDICATIONS and PRECAUTIONS, Drug Interactions for more information.)

Special Populations

Renal Insufficiency

 A pharmacokinetic study using a single 200 mg dose of itraconazole (four 50 mg capsules) was conducted in three groups of patients with renal impairment (uremia: n=7; hemodialysis: n=7; and continuous ambulatory peritoneal dialysis: n=5). In uremic subjects with a mean creatinine clearance of 13 mL/min. × 1.73m2, the bioavailability was slightly reduced compared with normal population parameters. This study did not demonstrate any significant effect of hemodialysis or continuous ambulatory peritoneal dialysis on the pharmacokinetics of itraconazole (Tmax, Cmax and AUC0-8). Plasma concentration-versus-time profiles showed wide intersubject variation in all three groups.

Hepatic Insufficiency 

A pharmacokinetic study using a single 100 mg dose of itraconazole (one 100 mg capsule) was conducted in 6 healthy and 12 cirrhotic subjects. No statistically significant differences in AUC were seen between these two groups. A statistically significant reduction in mean Cmax (47%) and a twofold increase in the elimination half-life (37 ± 17 hours) of itraconazole were noted in cirrhotic subjects compared with healthy subjects. Patients with impaired hepatic function should be carefully monitored when taking itraconazole. The prolonged elimination half-life of itraconazole observed in cirrhotic patients should be considered when deciding to initiate therapy with other medications metabolized by CYP3A4. (See BOX WARNING; CONTRAINDICATIONS and PRECAUTIONS, Drug Interactions.)

Decreased Cardiac Contractility

When itraconazole was administered intravenously to anesthetized dogs, a dose-related negative inotropic effect was documented. In a healthy volunteer study of itraconazole injection (intravenous infusion), transient, asymptomatic decreases in left ventricular ejection fraction were observed using gated SPECT imaging; these resolved before the next infusion, 12 hours later. If signs or symptoms of congestive heart failure appear during administration of itraconazole capsules, itraconazole should be discontinued. (See CONTRAINDICATIONS; WARNINGS; PRECAUTIONS, Drug Interactions and ADVERSE REACTIONS, Post-Marketing Experience for more information.)

MICROBIOLOGY

Mechanism of Action

In vitro studies have demonstrated that itraconazole inhibits the cytochrome P450-dependent synthesis of ergosterol, which is a vital component of fungal cell membranes.

Activity In Vitro and In Vivo

 Itraconazole exhibits in vitro activity against Blastomyces dermatitidis, Histoplasma capsulatum, Histoplasma duboisii, Aspergillus flavus, Aspergillus fumigatus, Candida albicans and Cryptococcus neoformans. Itraconazole also exhibits varying in vitro activity against Sporothrix schenckii, Trichophyton species, Candida krusei and other Candida species. The bioactive metabolite, hydroxyitraconazole, has not been evaluated against Histoplasma capsulatum and Blastomyces dermatitidis. Correlation between minimum inhibitory concentration (MIC) results in vitro and clinical outcome has yet to be established for azole antifungal agents.


Itraconazole administered orally was active in a variety of animal models of fungal infection using standard laboratory strains of fungi. Fungistatic activity has been demonstrated against disseminated fungal infections caused by Blastomyces dermatitidis, Histoplasma duboisii, Aspergillus fumigatus, Coccidioides immitis, Cryptococcus neoformans, Paracoccidioides brasiliensis, Sporothrix schenckii, Trichophyton rubrum and Trichophyton mentagrophytes.

Itraconazole administered at 2.5 mg/kg and 5 mg/kg via the oral and parenteral routes increased survival rates and sterilized organ systems in normal and immunosuppressed guinea pigs with disseminated Aspergillus fumigatus infections. Oral itraconazole administered daily at 40 mg/kg and 80 mg/kg increased survival rates in normal rabbits with disseminated disease and in immunosuppressed rats with pulmonary Aspergillus fumigatus infection, respectively. Itraconazole has demonstrated antifungal activity in a variety of animal models infected with Candida albicans and other Candida species.

Resistance

Isolates from several fungal species with decreased susceptibility to itraconazole have been isolated in vitro and from patients receiving prolonged therapy.

Several in vitro studies have reported that some fungal clinical isolates, including Candida species, with reduced susceptibility to one azole antifungal agent may also be less susceptible to other azole derivatives. The finding of cross-resistance is dependent on a number of factors, including the species evaluated, its clinical history, the particular azole compounds compared and the type of susceptibility test that is performed. The relevance of these in vitro susceptibility data to clinical outcome remains to be elucidated.

Studies (both in vitro and in vivo) suggest that the activity of amphotericin B may be suppressed by prior azole antifungal therapy. As with other azoles, itraconazole inhibits the 14C-demethylation step in the synthesis of ergosterol, a cell wall component of fungi. Ergosterol is the active site for amphotericin B. In one study the antifungal activity of amphotericin B against Aspergillus fumigatus infections in mice was inhibited by ketoconazole therapy. The clinical significance of test results obtained in this study is unknown.

INDICATIONS AND USAGE

Itraconazole capsules are indicated for the treatment of the following fungal infections in immunocompromised and non-immunocompromised patients:

  1. Blastomycosis, pulmonary and extrapulmonary;
  2. Histoplasmosis, including chronic cavitary pulmonary disease and disseminated, non-meningeal histoplasmosis and
  3. Aspergillosis, pulmonary and extrapulmonary, in patients who are intolerant of or who are refractory to amphotericin B therapy.

Specimens for fungal cultures and other relevant laboratory studies (wet mount, histopathology, serology) should be obtained before therapy to isolate and identify causative organisms. Therapy may be instituted before the results of the cultures and other laboratory studies are known; however, once these results become available, antiinfective therapy should be adjusted accordingly.

Itraconazole capsules are also indicated for the treatment of the following fungal infections in non-immunocompromised patients:

  1. Onychomycosis of the toenail, with or without fingernail involvement, due to dermatophytes (tinea unguium) and
  2. Onychomycosis of the fingernail due to dermatophytes (tinea unguium).

Prior to initiating treatment, appropriate nail specimens for laboratory testing (KOH preparation, fungal culture or nail biopsy) should be obtained to confirm the diagnosis of onychomycosis. (See CLINICAL PHARMACOLOGY, Special Populations; CONTRAINDICATIONS; WARNINGS and ADVERSE REACTIONS, Post-Marketing Experience for more information.)

Description of Clinical Studies

Blastomycosis

Analyses were conducted on data from two open-label, non-concurrently controlled studies (N=73 combined) in patients with normal or abnormal immune status. The median dose was 200 mg/day. A response for most signs and symptoms was observed within the first 2 weeks, and all signs and symptoms cleared between 3 and 6 months. Results of these two studies demonstrated substantial evidence of the effectiveness of itraconazole for the treatment of blastomycosis, compared with the natural history of untreated cases.

Histoplasmosis

Analyses were conducted on data from two open-label, non-concurrently controlled studies (N=34 combined) in patients with normal or abnormal immune status (not including HIV-infected patients). The median dose was 200 mg/day. A response for most signs and symptoms was observed within the first 2 weeks, and all signs and symptoms cleared between 3 and 12 months. Results of these two studies demonstrated substantial evidence of the effectiveness of itraconazole, for the treatment of histoplasmosis, compared with the natural history of untreated cases.

Histoplasmosis in HIV-Infected Patients

Data from a small number of HIV-infected patients suggested that the response rate of histoplasmosis in HIV-infected patients is similar to that of non-HIV-infected patients. The clinical course of histoplasmosis in HIV-infected patients is more severe and usually requires maintenance therapy to prevent relapse.

Aspergillosis

Analyses were conducted on data from an open-label, “single-patient-use” protocol designed to make itraconazole available in the U.S. for patients who either failed or were intolerant of amphotericin B therapy (N=190). The findings were corroborated by two smaller open-label studies (N=31 combined) in the same patient population. Most adult patients were treated with a daily dose of 200 mg to 400 mg, with a median duration of 3 months. Results of these studies demonstrated substantial evidence of effectiveness of itraconazole as a second-line therapy for the treatment of aspergillosis compared with the natural history of the disease in patients who either failed or were intolerant of amphotericin B therapy.

Onychomycosis of the Toenail

Analyses were conducted on data from three double-blind, placebo-controlled studies (N=214 total; 110 given itraconazole capsules) in which patients with onychomycosis of the toenails received 200 mg of itraconazole capsules once daily for 12 consecutive weeks. Results of these studies demonstrated mycologic cure, defined as simultaneous occurrence of negative KOH plus negative culture, in 54% of patients. Thirty-five percent (35%) of patients were considered an overall success (mycologic cure plus clear or minimal nail involvement with significantly decreased signs) and 14% of patients demonstrated mycologic cure plus clinical cure (clearance of all signs, with or without residual nail deformity). The mean time to overall success was approximately 10 months. Twenty-one percent (21%) of the overall success group had a relapse (worsening of the global score or conversion of KOH or culture from negative to positive).

Onychomycosis of the Fingernail

Analyses were conducted on data from a double-blind, placebo-controlled study (N=73 total; 37 given itraconazole capsules) in which patients with onychomycosis of the fingernails received a 1-week course (pulse) of 200 mg of itraconazole capsules b.i.d., followed by a 3-week period without itraconazole, which was followed by a second 1-week pulse of 200 mg of itraconazole capsules b.i.d. Results demonstrated mycologic cure in 61% of patients. Fifty-six percent (56%) of patients were considered an overall success and 47% of patients demonstrated mycologic cure plus clinical cure. The mean time to overall success was approximately 5 months. None of the patients who achieved overall success relapsed.

CONTRAINDICATIONS

Congestive Heart Failure

Itraconazole capsules should not be administered for the treatment of onychomycosis in patients with evidence of ventricular dysfunction such as congestive heart failure (CHF) or a history of CHF. (See CLINICAL PHARMACOLOGY, Special Populations; WARNINGS; PRECAUTIONS, Drug Interactions -Calcium Channel Blockers and ADVERSE REACTIONS, Post-Marketing Experience.)

Drug Interactions

Concomitant administration of itraconazole capsules, injection or oral solution and certain drugs metabolized by the cytochrome P450 3A4 isoenzyme system (CYP3A4) may result in increased plasma concentrations of those drugs, leading to potentially serious and/or life-threatening adverse events. Cisapride, oral midazolam, nisoldipine, pimozide, quinidine, dofetilide, triazolam and levacetylmethadol (levomethadyl) are contraindicated with itraconazole. HMG CoA-reductase inhibitors metabolized by CYP3A4, such as lovastatin and simvastatin, are also contraindicated with itraconazole. Ergot alkaloids metabolized by CYP3A4 such as dihydroergotamine, ergometrine (ergonovine), ergotamine and methylergometrine (methylergonovine) are contraindicated with itraconazole. (See BOX WARNING and PRECAUTIONS, Drug Interactions.)

Itraconazole should not be administered for the treatment of onychomycosis to pregnant patients or to women contemplating pregnancy.

Itraconazole is contraindicated for patients who have shown hypersensitivity to itraconazole or its excipients. There is no information regarding cross-hypersensitivity between itraconazole and other azole antifungal agents. Caution should be used when prescribing itraconazole to patients with hypersensitivity to other azoles.

WARNINGS

Itraconazole capsules and itraconazole oral solution should not be used interchangeably. This is because drug exposure is greater with the oral solution than with the capsules when the same dose of drug is given. In addition, the topical effects of mucosal exposure may be different between the two formulations. Only the oral solution has been demonstrated effective for oral and/or esophageal candidiasis.

Hepatic Ef fects

Itraconazole has been associated with rare cases of serious hepatotoxicity, including liver failure and death. Some of these cases had neither pre-existing liver disease nor a serious underlying medical condition and some of these cases developed within the first week of treatment. If clinical signs or symptoms develop that are consistent with liver disease, treatment should be discontinued and liver function testing performed. Continued itraconazole use or reinstitution of treatment with itraconazole is strongly discouraged unless there is a serious or life threatening situation where the expected benefit exceeds the risk. (See PRECAUTIONS, Information for Patients and ADVERSE REACTIONS.)

Cardiac Dysrhythmias

Life-threatening cardiac dysrhythmias and/or sudden death have occurred in patients using cisapride, pimozide, levacetylmethadol (levomethadyl) or quinidine concomitantly with itraconazole and/or other CYP3A4 inhibitors. Concomitant administration of these drugs with itraconazole is contraindicated. (See BOX WARNING; CONTRAINDICATIONS and PRECAUTIONS, Drug Interactions.)

Car diac Disease

Itraconazole capsules should not be administered for the treatment of onychomycosis in patients with evidence of ventricular dysfunction such as congestive heart failure (CHF) or a history of CHF. Itraconazole capsules should not be used for other indications in patients with evidence of ventricular dysfunction unless the benefit clearly outweighs the risk.

For patients with risk factors for congestive heart failure, physicians should carefully review the risks and benefits of itraconazole therapy. These risk factors include cardiac disease such as ischemic and valvular disease; significant pulmonary disease such as chronic obstructive pulmonary disease; and renal failure and other edematous disorders. Such patients should be informed of the signs and symptoms of CHF, should be treated with caution, and should be monitored for signs and symptoms of CHF during treatment. If signs or symptoms of CHF appear during administration of itraconazole capsules, discontinue administration.

When itraconazole was administered intravenously to anesthetized dogs, a dose-related negative inotropic effect was documented. In a healthy volunteer study of itraconazole injection (intravenous infusion), transient, asymptomatic decreases in left ventricular ejection fraction were observed using gated SPECT imaging; these resolved before the next infusion, 12 hours later.

Itraconazole   has been associated with reports of congestive heart failure. In post-marketing experience, heart failure was more frequently reported in patients receiving a total daily dose of 400 mg than among those receiving lower total daily doses. This suggests that the risk of heart failure might increase with the total daily dose of itraconazole.

Calcium channel blockers can have negative inotropic effects which may be additive to those of itraconazole. In addition, itraconazole can inhibit the metabolism of calcium channel blockers. Therefore, caution should be used when co-administering itraconazole and calcium channel blockers due to an increased risk of CHF. Concomitant administration of itraconazole and nisoldipine is contraindicated.

Cases of CHF, peripheral edema and pulmonary edema have been reported in the post-marketing period among patients being treated for onychomycosis and/or systemic fungal infections. (See CLINICAL PHARMACOLOGY, Special Populations; CONTRAINDICATIONS; PRECAUTIONS, Drug Interactions and ADVERSE REACTIONS, Post-Marketing Experience for more information.)

PRECAUTIONS

Ge neral

Rare cases of serious hepatotoxicity have been observed with itraconazole treatment, including some cases within the first week. In patients with elevated or abnormal liver enzymes or active liver disease or who have experienced liver toxicity with other drugs, treatment with itraconazole is strongly discouraged unless there is a serious or life threatening situation where the expected benefit exceeds the risk. Liver function monitoring should be done in patients with pre-existing hepatic function abnormalities or those who have experienced liver toxicity with other medications and should be considered in all patients receiving itraconazole. Treatment should be stopped immediately and liver function testing should be conducted in patients who develop signs and symptoms suggestive of liver dysfunction.

If neuropathy occurs that may be attributable to itraconazole capsules, the treatment should be discontinued.

Itraconazole capsules should be administered after a full meal. (See CLINICAL PHARMACOLOGY, Pharmacokinetics and Metabolism.)

Under fasted conditions, itraconazole absorption was decreased in the presence of decreased gastric acidity. The absorption of itraconazole may be decreased with the concomitant administration of antacids or gastric acid secretion suppressors. Studies conducted under fasted conditions demonstrated that administration with 8 ounces of a cola beverage resulted in increased absorption of itraconazole in AIDS patients with relative or absolute achlorhydria. This increase relative to the effects of a full meal is unknown. (See CLINICAL PHARMACOLOGY, Pharmacokinetics and Metabolism.)

Transient or permanent hearing loss has been reported in patients receiving treatment with itraconazole. Several of these reports included concurrent administration of quinidine which is contraindicated (see BOX WARNINGS, Drug Interactions; CONTRAINDICATIONS, Drug Interactions and PRECAUTIONS, Drug Interactions). The hearing loss usually resolves when treatment is stopped, but can persist in some patients. Patients should be informed of this potential side effect and advised to discontinue therapy and inform their physicians if any hearing loss symptoms occur.

Information for Patients


Drug Interactions

Itraconazole and its major metabolite, hydroxyitraconazole, are inhibitors of CYP3A4. Therefore, the following drug interactions may occur

(See Table 1. Selected Drugs that are predicted to alter the plasma concentration of itraconazole or have their plasma concentration altered by itraconazolea below and the following drug class subheadings that follow):

  1. Itraconazole may decrease the elimination of drugs metabolized by CYP3A4, resulting in increased plasma concentrations of these drugs when they are administered with itraconazole. These elevated plasma concentrations may increase or prolong both therapeutic and adverse effects of these drugs. Whenever possible, plasma concentrations of these drugs should be monitored, and dosage adjustments made after concomitant itraconazole therapy is initiated. When appropriate, clinical monitoring for signs or symptoms of increased or prolonged pharmacologic effects is advised. Upon discontinuation, depending on the dose and duration of treatment, itraconazole plasma concentrations decline gradually (especially in patients with hepatic cirrhosis or in those receiving CYP3A4 inhibitors). This is particularly important when initiating therapy with drugs whose metabolism is affected by itraconazole.
  2. Inducers of CYP3A4 may decrease the plasma concentrations of itraconazole. Itraconazole may not be effective in patients concomitantly taking itraconazole and one of these drugs. Therefore, administration of these drugs with itraconazole is not recommended.
  3. Other inhibitors of CYP3A4 may increase the plasma concentrations of itraconazole. Patients who must take itraconazole concomitantly with one of these drugs should be monitored closely for signs or symptoms of increased or prolonged pharmacologic effects of itraconazole.
Table 1. Selected Drugs that are predicted to alter the plasma concentration of itraconazole or have their plasma concentration altered by itraconazole*
*
This list is not all-inclusive.
Contraindicated with itraconazole based on clinical and/or pharmacokinetics studies. (See WARNINGS and below.)
For information on parenterally administered midazolam, see the Benzodiazepine paragraph below.
Drug plasma concentration increased by itraconazole
Antiarrhythmicsdigoxin, dofetilide, quinidine, disopyramide
Anticonvulsantscarbamazepine
Antimycobacterialsrifabutin
Antineoplasticsbusulfan, docetaxel, vinca alkaloids
Antipsychoticspimozide
Benzodiazepinesalprazolam, diazepam, midazolam,, triazolam
Calcium Channel Blockersdihydropyridines (including nisoldipine), verapamil
Gastrointestinal Motility Agentscisapride
HMG CoA-Reductase Inhibitorsatorvastatin, cerivastatin, lovastatin, simvastatin
Immunosuppressantscyclosporine, tacrolimus, sirolimus
Oral Hypoglycemicsoral hypoglycemics
Protease Inhibitorsindinavir, ritonavir, saquinavir
Otherlevacetylmethadol (levomethadyl), ergot alkaloids, halofantrine, alfentanil, buspirone, methylprednisolone, budesonide, dexamethasone, fluticasone, trimetrexate, warfarin, cilostazol, eletriptan, fentanyl
Decrease plasma concentration of itraconazole
Anticonvulsantscarbamazepine, phenobarbital, phenytoin
Antimycobacterialsisoniazid, rifabutin, rifampin
Gastric Acid Suppressors/Neutralizersantacids, H2-receptor antagonists, proton pump inhibitors
Non-nucleoside Reverse Transcriptase Inhibitorsnevirapine
Increase plasma concentration of itraconazole
Macrolide Antibioticsclarithromycin, erythromycin
Protease Inhibitorsindinavir, ritonavir

Antiarrhythmics

The class IA antiarrhythmic quinidine and class III antiarrhythmic dofetilide are known to prolong the QT interval. Co-administration of quinidine or dofetilide with itraconazole may increase plasma concentrations of quinidine or dofetilide which could result in serious cardiovascular events. Therefore, concomitant administration of itraconazole and quinidine or dofetilide is contraindicated. (See BOX WARNING, CONTRAINDICATIONS and WARNINGS.)

The class IA antiarrhythmic disopyramide has the potential to increase the QT interval at high plasma concentrations. Caution is advised when itraconazole and disopyramide are administered concomitantly.

Concomitant administration of digoxin and itraconazole has led to increased plasma concentrations of digoxin.

Anticonvulsants

Reduced plasma concentrations of itraconazole were reported when itraconazole was administered concomitantly with phenytoin. Carbamazepine, phenobarbital and phenytoin are all inducers of CYP3A4. Although interactions with carbamazepine and phenobarbital have not been studied, concomitant administration of itraconazole and these drugs would be expected to result in decreased plasma concentrations of itraconazole. In addition, in vivo studies have demonstrated an increase in plasma carbamazepine concentrations in subjects concomitantly receiving ketoconazole. Although there are no data regarding the effect of itraconazole on carbamazepine metabolism, because of the similarities between ketoconazole and itraconazole, concomitant administration of itraconazole and carbamazepine may inhibit the metabolism of carbamazepine.

Antimycobacterials

 Drug interaction studies have demonstrated that plasma concentrations of azole antifungal agents and their metabolites, including itraconazole and hydroxyitraconazole, were significantly decreased when these agents were given concomitantly with rifabutin or rifampin. In vivo data suggest that rifabutin is metabolized in part by CYP3A4. Itraconazole may inhibit the metabolism of rifabutin. Although no formal study data are available for isoniazid, similar effects should be anticipated. Therefore, the efficacy of itraconazole could be substantially reduced if given concomitantly with one of these agents. Co-administration is not recommended.

Antineoplastics

Itraconazole may inhibit the metabolism of busulfan, docetaxel and vinca alkaloids.

Antipsychotics

Pimozide is known to prolong the QT interval and is partially metabolized by CYP3A4. Co-administration of pimozide with itraconazole could result in serious cardiovascular events. Therefore, concomitant administration of itraconazole and pimozide is contraindicated. (See BOX WARNING, CONTRAINDICATIONS and WARNINGS.)

Benzodiazepines

Concomitant administration of itraconazole and alprazolam, diazepam, oral midazolam or triazolam could lead to increased plasma concentrations of these benzodiazepines. Increased plasma concentrations could potentiate and prolong hypnotic and sedative effects. Concomitant administration of itraconazole and oral midazolam or triazolam is contraindicated. (See CONTRAINDICATIONS and WARNINGS.) If midazolam is administered parenterally, special precaution and patient monitoring is required since the sedative effect may be prolonged.

Calcium Channel Blockers

Edema has been reported in patients concomitantly receiving itraconazole and dihydropyridine calcium channel blockers. Appropriate dosage adjustment may be necessary.

Calcium channel blockers can have a negative inotropic effect which may be additive to those of itraconazole; itraconazole can inhibit the metabolism of calcium channel blockers such as dihydropyridines (e.g., nifedipine and felodipine) and verapamil. Therefore, caution should be used when co-administering itraconazole and calcium channel blockers due to an increased risk of CHF. Concomitant administration of itraconazole and nisoldipine is contraindicated. (See CLINICAL PHARMACOLOGY, Special Populations; CONTRAINDICATIONS; WARNINGS and ADVERSE REACTIONS, Post-Marketing Experience for more information.)

Gastric Acid Suppressors/Neutralizers

Reduced plasma concentrations of itraconazole were reported when itraconazole capsules were administered concomitantly with H2-receptor antagonists. Studies have shown that absorption of itraconazole is impaired when gastric acid production is decreased. Therefore, itraconazole should be administered with a cola beverage if the patient has achlorhydria or is taking H2-receptor antagonists or other gastric acid suppressors. Antacids should be administered at least 1 hour before or 2 hours after administration of itraconazole capsules. In a clinical study, when itraconazole capsules were administered with omeprazole (a proton pump inhibitor), the bioavailability of itraconazole was significantly reduced.

Gastrointestinal Motility Agents

 Co-administration of itraconazole with cisapride can elevate plasma cisapride concentrations which could result in serious cardiovascular events. Therefore, concomitant administration of itraconazole with cisapride is contraindicated. (See BOX WARNING, CONTRAINDICATIONSandWARNINGS.)

HMG CoA-Reductase Inhibitors

Human pharmacokinetic data suggest that itraconazole inhibits the metabolism of atorvastatin, cerivastatin, lovastatin and simvastatin, which may increase the risk of skeletal muscle toxicity, including rhabdomyolysis. Concomitant administration of itraconazole with HMG CoA-reductase inhibitors, such as lovastatin and simvastatin, is contraindicated. (See CONTRAINDICATIONSand WARNINGS.)

Concomitant administration of itraconazole and cyclosporine or tacrolimus has led to increased plasma concentrations of these immunosuppressants. Concomitant administration of itraconazole and sirolimus could increase plasma concentrations of sirolimus.

Macrolide Antibiotics

Erythromycin and clarithromycin are known inhibitors of CYP3A4 (See Table 1. Selected Drugs that are predicted to alter the plasma concentration of itraconazole or have their plasma concentration altered by itraconazolea ) and may increase plasma concentrations of itraconazole. In a small pharmacokinetic study involving HIV infected patients, clarithromycin was shown to increase plasma concentrations of itraconazole. Similarly, following administration of 1 gram of erythromycin ethyl succinate and 200 mg itraconazole as single doses, the mean Cmax and AUC0-∞ of itraconazole increased by 44% (90% CI: 119% to 175%) and 36% (90% CI: 108% to 171%), respectively.

Non-Nucleoside Reverse Transcriptase Inhibitors

Nevirapine is an inducer of CYP3A4. In vivo studies have shown that nevirapine induces the metabolism of ketoconazole, significantly reducing the bioavailability of ketoconazole. Studies involving nevirapine and itraconazole have not been conducted. However, because of the similarities between ketoconazole and itraconazole, concomitant administration of itraconazole and nevirapine is not recommended.

In a clinical study, when 8 HIV-infected subjects were treated concomitantly with itraconazole capsules 100 mg twice daily and the nucleoside reverse transcriptase inhibitor zidovudine 8 ± 0.4 mg/kg/day, the pharmacokinetics of zidovudine were not affected. Other nucleoside reverse transcriptase inhibitors have not been studied.

Oral Hypoglycemic Agents

Severe hypoglycemia has been reported in patients concomitantly receiving azole antifungal agents and oral hypoglycemic agents. Blood glucose concentrations should be carefully monitored when itraconazole and oral hypoglycemic agents are co-administered.

Polyenes

Prior treatment with itraconazole, like other azoles, may reduce or inhibit the activity of polyenes such as amphotericin B. However, the clinical significance of this drug effect has not been clearly defined.

Protease Inhibitors

Concomitant administration of itraconazole and protease inhibitors metabolized by CYP3A4, such as indinavir, ritonavir and saquinavir, may increase plasma concentrations of these protease inhibitors. In addition, concomitant administration of itraconazole and indinavir and ritonavir (but not saquinavir) may increase plasma concentrations of itraconazole. Caution is advised when itraconazole and protease inhibitors must be given concomitantly.

Other

Carcinogenesis, Mutagenesis and Impairment of Fertility

Itraconazole showed no evidence of carcinogenicity potential in mice treated orally for 23 months at dosage levels up to 80 mg/kg/day (approximately 10 x the maximum recommended human dose [MRHD]). Male rats treated with 25 mg/kg/day (3.1 x MRHD) had a slightly increased incidence of soft tissue sarcoma. These sarcomas may have been a consequence of hypercholesterolemia, which is a response of rats, but not dogs or humans, to chronic itraconazole administration. Female rats treated with 50 mg/kg/day (6.25 x MRHD) had an increased incidence of squamous cell carcinoma of the lung (2/50) as compared to the untreated group. Although the occurrence of squamous cell carcinoma in the lung is extremely uncommon in untreated rats, the increase in this study was not statistically significant.

Itraconazole produced no mutagenic effects when assayed in a DNA repair test (unscheduled DNA synthesis) in primary rat hepatocytes, in Ames tests with Salmonella typhimurium (6 strains) and Escherichia coli, in the mouse lymphoma gene mutation tests, in a sex-linked recessive lethal mutation (Drosophila melanogaster) test, in chromosome aberration tests in human lymphocytes, in a cell transformation test with C3H/10T½ C18 mouse embryo fibroblasts cells, in a dominant lethal mutation test in male and female mice, and in micronucleus tests in mice and rats.

Itraconazole did not affect the fertility of male or female rats treated orally with dosage levels of up to 40 mg/kg/day (5 x MRHD), even though parental toxicity was present at this dosage level. More severe signs of parental toxicity, including death, were present in the next higher dosage level, 160 mg/kg/day (20 x MRHD).

Pregnancy

Teratogenic Effects

Pregnancy Category C

 Itraconazole was found to cause a dose-related increase in maternal toxicity, embryotoxicity and teratogenicity in rats at dosage levels of approximately 40 mg/kg/day to 160 mg/kg/day (5 to 20 x MRHD) and in mice at dosage levels of approximately 80 mg/kg/day (10 x MRHD). In rats, the teratogenicity consisted of major skeletal defects; in mice, it consisted of encephaloceles and/or macroglossia.

There are no studies in pregnant women. Itraconazole should be used for the treatment of systemic fungal infections in pregnancy only if the benefit outweighs the potential risk.

Itraconazole should not be administered for the treatment of onychomycosis to pregnant patients or to women contemplating pregnancy. Itraconazole should not be administered to women of childbearing potential for the treatment of onychomycosis unless they are using effective measures to prevent pregnancy and they begin therapy on the second or third day following the onset of menses. Effective contraception should be continued throughout itraconazole therapy and for 2 months following the end of treatment.

During post-marketing experience, cases of congenital abnormalities have been reported. (See ADVERSE REACTIONS, Post-Marketing Experience.)

Nursing Mothers

Itraconazole is excreted in human milk; therefore, the expected benefits of itraconazole therapy for the mother should be weighed against the potential risk from exposure of itraconazole to the infant. The U.S. Public Health Service Centers for Disease Control and Prevention advises HIV-infected women not to breast-feed to avoid potential transmission of HIV to uninfected infants.

Pediatric Use

The efficacy and safety of itraconazole have not been established in pediatric patients. No pharmacokinetic data on itraconazole capsules are available in children. A small number of patients ages 3 to 16 years have been treated with 100 mg/day of itraconazole capsules for systemic fungal infections, and no serious unexpected adverse events have been reported. Itraconazole oral solution (5 mg/kg/day) has been administered to pediatric patients (N=26; ages 6 months to 12 years) for 2 weeks and no serious unexpected adverse events were reported.

The long-term effects of itraconazole on bone growth in children are unknown. In three toxicology studies using rats, itraconazole induced bone defects at dosage levels as low as 20 mg/kg/day (2.5 x MRHD). The induced defects included reduced bone plate activity, thinning of the zona compacta of the large bones and increased bone fragility. At a dosage level of 80 mg/kg/day (10 x MRHD) over 1 year or 160 mg/kg/day (20 x MRHD) for 6 months, itraconazole induced small tooth pulp with hypocellular appearance in some rats. No such bone toxicity has been reported in adult patients.

HIV-Infected Patients

Because hypochlorhydria has been reported in HIV-infected individuals, the absorption of itraconazole in these patients may be decreased.

Renal Impairment

Limited data are available on the use of oral itraconazole in patients with renal impairment. Caution should be exercised when this drug is administered in this patient population. (See CLINICAL PHARMACOLOGY, Special Populations.)

Hepatic Impairment

Limited data are available on the use of oral itraconazole in patients with hepatic impairment. Caution should be exercised when this drug is administered in this patient population. (See CLINICAL PHARMACOLOGY, Special Populations.)

ADVERSE REACTIONS

Itraconazole has been associated with rare cases of serious hepatotoxicity, including liver failure and death. Some of these cases had neither pre-existing liver disease nor a serious underlying medical condition. If clinical signs or symptoms develop that are consistent with liver disease, treatment should be discontinued and liver function testing performed. The risks and benefits of itraconazole use should be reassessed. (See WARNINGS, Hepatic Ef fects and PRECAUTIONS, Ge neraland Information for Patients.)

Adverse Events in the Treatment of Systemic Fungal Infections

Adverse event data were derived from 602 patients treated for systemic fungal disease in U.S. clinical trials who were immunocompromised or receiving multiple concomitant medications. Treatment was discontinued in 10.5% of patients due to adverse events. The median duration before discontinuation of therapy was 81 days (range: 2 to 776 days). The table lists adverse events reported by at least 1% of patients.

Clinical Trials of Systemic Fungal Infections: Adverse Events Occurring with an Incidence of Greater than or Equal to 1%
*
Rash tends to occur more frequently in immunocompromised patients receiving immunosuppressive medications.
Body System / Adverse Event

Incidence

(%) (N=602)

Gastrointestinal

Nausea

Vomiting

Diarrhea

Abdominal Pain

Anorexia

11

5

3

2

1

Body as a Whole

Edema

Fatigue

Fever

Malaise

4

3

3

1

Skin and Appendages

Rash*

Pruritus

9

3

Central/Peripheral Nervous System

Headache

Dizziness

4

2

Psychiatric

Libido Decreased

Somnolence

1

1

Cardiovascular

Hypertension
3

Metabolic/Nutritional

Hypokalemia
2

Urinary System

Albuminuria
1

Liver and Biliary System

Hepatic Function Abnormal
3

Reproductive System, Male

Impotence
1

Adverse events infrequently reported in all studies included constipation, gastritis, depression, insomnia, tinnitus, menstrual disorder, adrenal insufficiency, gynecomastia and male breast pain.

Adverse Events Reported in Toenail Onychomycosis Clinical Trials

Patients in these trials were on a continuous dosing regimen of 200 mg once daily for 12 consecutive weeks.

The following adverse events led to temporary or permanent discontinuation of therapy.

Clinical Trials of Onychomycosis of the Toenail: Adverse Events Leading to Temporary or Permanent Discontinuation of Therapy
Adverse EventIncidence (%) Itraconazole (N=112)
Elevated Liver Enzymes (greater than twice the upper limit of normal)4
Gastrointestinal Disorders4
Rash3
Hypertension2
Orthostatic Hypotension1
Headache1
Malaise1
Myalgia1
Vasculitis1
Vertigo1

The following adverse events occurred with an incidence of greater than or equal to 1% (N=112): headache 10%, rhinitis 9%, upper respiratory tract infection 8%, sinusitis, injury 7%, diarrhea, dyspepsia, flatulence, abdominal pain, dizziness, rash 4%, cystitis, urinary tract infection, liver function abnormality, myalgia, nausea 3%, appetite increased, constipation, gastritis, gastroenteritis, pharyngitis, asthenia, fever, pain, tremor, herpes zoster, abnormal dreaming 2%.

Adverse Events Reported in Fingernail Onychomycosis Clinical Trials

Patients in these trials were on a pulse regimen consisting of two 1-week treatment periods of 200 mg twice daily, separated by a 3-week period without drug.

The following adverse events led to temporary or permanent discontinuation of therapy.

Clinical Trials of Onychomycosis of the Fingernail: Adverse Events Leading to Temporary or Permanent Discontinuation of Therapy
Adverse Event

Incidence (%)

Itraconazole (N=37)
Rash/Pruritus3
Hypertriglyceridemia2

The following adverse events occurred with an incidence of greater than or equal to 1% (N=37): headache 8%, pruritus, nausea, rhinitis 5%, rash, bursitis, anxiety, depression, constipation, abdominal pain, dyspepsia, ulcerative stomatitis, gingivitis, hypertriglyceridemia, sinusitis, fatigue, malaise, pain, injury 3%.

Post-Marketing Experience

Worldwide post-marketing experiences with the use of itraconazole include very rare reports (<1/10,000) of the adverse events listed below:

Post-Marketing Reports of Adverse Drug Reactions
Blood and Lymphatic System Disorders
Very rareLeukopenia, neutropenia, thrombocytopenia
Immune System Disorders
Very rareSerum sickness; angioneurotic edema; anaphylaxis; anaphylactic, anaphylactoid and allergic reactions
Metabolism and Nutrition Disorders
Very rareHypertriglyceridemia, hypokalemia
Nervous System Disorders
Very rarePeripheral neuropathy, paresthesia, hypoesthesia, headache, dizziness
Eye Disorders
Very rareVisual disturbances, including vision blurred and diplopia
Ear and Labyrinth Disorder
Very rareTinnitus, transient or permanent hearing loss
Cardiac Disorders
Very rareCongestive heart failure
Respiratory, Thoracic and Mediastinal Disorders
Very rarePulmonary edema

 

Gastrointestinal Disorders
Very rareAbdominal pain, vomiting, dyspepsia, nausea, diarrhea, constipation,dysgeusia
Hepato-Biliary Disorders
Very rareSerious hepatotoxicity (including some cases of fatal acute liver failure), hepatitis, reversible increases in hepatic enzymes
Skin and Subcutaneous Tissue Disorders
Very rareToxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme, exfoliative dermatitis, leukocytoclastic vasculitis, urticaria, alopecia, photosensitivity, rash, pruritus
Musculoskeletal and Connective Tissue Disorders
Very rareMyalgia, arthralgia
Renal and Urinary Disorders
Very rarePollakiuria, urinary incontinence
Reproductive System and Breast Disorders
Very rareMenstrual disorders, erectile dysfunction
General Disorders and Administration Site Conditions
Very rarePeripheral edema

There is limited information on the use of itraconazole during pregnancy. Cases of congenital abnormalities including skeletal, genitourinary tract, cardiovascular and ophthalmic malformations as well as chromosomal and multiple malformations have been reported during post-marketing experience. A causal relationship with itraconazole has not been established. (See CLINICAL PHARMACOLOGY, Special Populations; CONTRAINDICATIONS; WARNINGSand PRECAUTIONS, Drug Interactions for more information.)

OVERDOSAGE 

Itraconazole is not removed by dialysis. In the event of accidental overdosage, supportive measures, including gastric lavage with sodium bicarbonate, should be employed.

Limited data exist on the outcomes of patients ingesting high doses of itraconazole. In patients taking either 1,000 mg of itraconazole oral solution or up to 3,000 mg of itraconazole capsules, the adverse event profile was similar to that observed at recommended doses.

DOSAGE AND ADMINISTRATION

Itraconazole capsules should be taken with a full meal to ensure maximal absorption.

Itraconazole capsules are a different preparation than itraconazole oral solution and should not be used interchangeably.

Treatment of Blastomycosis and Histoplasmosis

The recommended dose is 200 mg once daily (2 capsules). If there is no obvious improvement or there is evidence of progressive fungal disease, the dose should be increased in 100 mg increments to a maximum of 400 mg daily. Doses above 200 mg/day should be given in two divided doses.

Treatment of Aspergillosis

A daily dose of 200 mg to 400 mg is recommended.

Treatment in Life-Threatening Situations

In life-threatening situations, a loading dose should be used whether given as oral capsules or intravenously.

Treatment should be continued for a minimum of three months and until clinical parameters and laboratory tests indicate that the active fungal infection has subsided. An inadequate period of treatment may lead to recurrence of active infection.

Itraconazole capsules and itraconazole oral solution should not be used interchangeably. Only the oral solution has been demonstrated effective for oral and/or esophageal candidiasis.

Treatment of Onychomycosis

Toenails with or without fingernail involvement: The recommended dose is 200 mg (2 capsules) once daily for 12 consecutive weeks.

Treatment of Onychomycosis

Fingernails only: The recommended dosing regimen is 2 treatment regimens pulses, each consisting of 200 mg (2 capsules) b.i.d. (400 mg/day) for 1 week. The pulses are separated by a 3-week period without itraconazole.

HOW SUPPLIED

Itraconazole capsules are available containing 100 mg of itraconazole, with an aqua blue opaque cap, light blue clear body, imprinted “E550” in black ink on cap and body, filled with white to off-white pellets. Itraconazole capsules are supplied in bottles of 28, 30, 100 and 500 capsules and in a 7-Day Treatment Pack (cartons containing 7 blister packs of 4 capsules each).

Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature].

Protect from light and moisture.

Patient Information

Itraconazole Capsules, 100 mg

This summary contains important information about Itraconazole Capsules.

This information is for patients who have been prescribed itraconazole to treat fungal nail infections. If your doctor prescribed itraconazole for medical problems other than fungal nail infections, ask your doctor if there is any information in this summary that does not apply to you. Read this information carefully each time you start to use itraconazole capsules. This information does not take the place of discussion between you and your doctor. Only your doctor can decide if itraconazole is the right treatment for you. If you do not understand some of this information or have any questions, talk with your doctor or pharmacist.

What Is The Most Important Information I Should Know About Itraconazole?

Itraconazole is used to treat fungal nail infections. However, itraconazole is not for everyone. Do not take itraconazole for fungal nail infections if you have had heart failure, including congestive heart failure. You should not take itraconazole if you are taking certain medicines that could lead to serious or life-threatening medical problems. (See "Who Should Not Take Itraconazole?" below.)

If you have had heart, lung, liver, kidney or other serious health problems, ask your doctor if it is safe for you to take itraconazole.

What Happens If I Have A Fungal Nail Infection?

Anyone can have a fungal nail infection, but it is usually found in adults. When a fungus infects the tip or sides of a nail, the infected part of the nail may turn yellow or brown. If not treated, the fungus may spread under the nail towards the cuticle. If the fungus spreads, more of the nail may change color, may become thick or brittle and the tip of the nail may become raised. In some patients, this can cause pain and discomfort.

What Is Itraconazole?

Itraconazole is a prescription medicine used to treat fungal infections of the toenails and fingernails. It is also used to treat some types of fungal infections in other areas of your body. We do not know if itraconazole works in children with fungal nail infections or if it is safe for children to take.

Itraconazole comes in the form of capsules and liquid (oral solution). The capsule and liquid forms work differently, so you should not use one in place of the other. This Patient Information discusses only the capsule form of itraconazole. You will get these capsules in a medicine bottle or a 7-Day Treatment Pack. The 7-Day Treatment Pack contains 28 capsules for treatment of your fungal nail infection.

Itraconazole goes into your bloodstream and travels to the source of the infection underneath the nail so that it can fight the infection there. Improved nails may not be obvious for several months after the treatment period is finished because it usually takes about 6 months to grow a new fingernail and 12 months to grow a new toenail.

Who Should Not Take Itraconazole?

Itraconazole is not for everyone. Your doctor will decide if itraconazole is the right treatment for you. Some patients should not take itraconazole because they may have certain health problems or may be taking certain medicines that could lead to serious or life-threatening medical problems.

Tell your doctor and pharmacist the name of all the prescription and non-prescription medicines you are taking, including dietary supplements and herbal remedies. Also tell your doctor about any other medical conditions you have had, especially heart, lung, liver or kidney conditions.

Never take itraconazole if you:

Taking itraconazole with certain other medicines could lead to serious or life-threatening medical problems. For example, taking fentanyl, a strong opioid narcotic pain medicine, with itraconazole could cause serious side effects, including trouble breathing, that may be life-threatening. Tell your doctor and pharmacist the name of all the prescription and non-prescription medicines you are taking. Your doctor will decide if itraconazole is the right treatment for you.

What Should I Know About Itraconazole And Pregnancy Or Breast-Feeding?

Never take itraconazole if you have a fungal nail infection and are pregnant or planning to become pregnant within 2 months after you have finished your treatment.

If you are able to become pregnant, you should use effective birth control during itraconazole treatment and for 2 months after finishing treatment. Ask your doctor about effective types of birth control.

If you are breast-feeding, talk with your doctor about whether you should take itraconazole .

How Should I Take Itraconazole?

Always take Itraconazole Capsules during or right after a full meal.

Your doctor will decide the right dose for you. Depending on your infection, you will take itraconazole once a day for 12 weeks or twice a day for 1 week in a “pulse” dosing schedule. You will receive either a bottle of capsules or a 7-Day Treatment Pack. Do not skip any doses. Be sure to finish all your itraconazole as prescribed by your doctor.

If you have ever had liver problems, your doctor should do a blood test to check your condition. If you haven't had liver problems, your doctor may recommend blood tests to check the condition of your liver because patients taking itraconazole can develop liver problems.

If you forget to take or miss doses of Itraconazole Capsules, ask your doctor what you should do with the missed doses.

The Itraconazole Capsules 7-Day Treatment Pack

If you use the 7-Day Treatment Pack, you will take itraconazole for 1 week and then take no itraconazole for the next 3 weeks before repeating the 1-week treatment. This is called “pulse dosing.” The Itraconazole Capsules 7-Day Treatment Pack contains enough medicine for one week of treatment.

The itraconazole 7-Day Treatment Pack comes with special instructions. It contains 7 pouches-one for each day of treatment. Inside each pouch is a card containing 4 capsules. Looking at the back of the card, fold it back along the dashed line and peel away the backing so that you can remove 2 capsules.

Itraconazole Pulse Dosing
Take 2 Itraconazole Capsules twice a day for 1 week
Day 1Day 2Day 3Day 4Day 5Day 6Day 7
AMPMAMPMAMPMAMPMAMPMAMPMAMPM
Week 1

~

~

~

~

~

~

~

~

~

~

~

~

~

~

~

~

~

~

~

~

~

~

~

~

~

~

~

~

Week 2

For the next 3 weeks, do not take any itraconazole capsules.

Remember to get a refill before the end of Week 4

when your doctor prescribes another 7-Day Treatment Pack.
Week 3
Week 4

What Are The Possible Side Effects Of Itraconazole?

The most common side effects that cause people to stop treatment either for a short time or completely include: skin rash, high triglyceride test results, high liver test results and digestive system problems (such as nausea, bloating and diarrhea).

Stop Itraconazole Capsules and call your doctor or get medical assistance right away if you have a severe allergic reaction. Symptoms of an allergic reaction may include skin rash, itching, hives, shortness of breath or difficulty breathing and/or swelling of the face. Very rarely, an oversensitivity to sunlight, a tingling sensation in the limbs or a severe skin disorder can occur. If any of these symptoms occur, stop taking itraconazole and contact your doctor.

Stop Itraconazole Capsules and call your doctor right away if you develop shortness of breath; have unusual swelling of your feet, ankles or legs; suddenly gain weight; are unusually tired; cough up white or pink phlegm; have unusual fast heartbeats; or begin to wake up at night. In rare cases, patients taking itraconazole could develop serious heart problems and these could be warning signs of heart failure.

Stop Itraconazole Capsules and call your doctor right away if you experience any hearing loss symptoms. In very rare cases, patients taking itraconazole have reported temporary or permanent hearing loss.

Stop Itraconazole Capsules and call your doctor right away if you become unusually tired; lose your appetite or develop nausea, abdominal pain or vomiting, a yellow color to your skin or eyes or dark colored urine or pale stools (bowel movements). In rare cases, patients taking itraconazole could develop serious liver problems and these could be warning signs.

Call your doctor right away if you develop tingling or numbness in your extremities (hands or feet), if your vision gets blurry or you see double, if you hear a ringing in your ears, if you lose the ability to control your urine or urinate much more than usual.

Additional possible side effects include upset stomach, vomiting, abdominal pain, constipation, headache, menstrual disorders, erectile dysfunction, dizziness, muscle weakness or pain, painful joints, unpleasant taste or hair loss. These are not all the side effects of itraconazole. Your doctor or pharmacist can give you a more complete list.

What Should I Do If I Take An Overdose Of Itraconazole Capsules?

If you think you took too much itraconazole, call your doctor or local poison control center or go to the nearest hospital emergency room right away.

How Should I Store Itraconazole Capsules?

Keep all medicines, including itraconazole  , out of the reach of children.

Store Itraconazole Capsules and the 7-Day Treatment Pack at room temperature in a dry place away from light.

General Advice About Itraconazole Capsules

Medicines are sometimes prescribed for conditions that are not mentioned in patient information leaflets. Do not use itraconazole for a condition for which it was not prescribed. Do not give itraconazole to other people, even if they have the same symptoms you have. It may harm them.

This leaflet summarizes the most important information about itraconazole . If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for information about itraconazole that is written for health professionals.

This patient information has been approved by the U.S. Food and Drug Administration.

The following are registered trademarks of their respective manufacturers:

Mevacor® (Merck & Co., Inc.), Advicor® (Kos Pharmaceuticals, Inc.), Altocor™ (Andrx Laboratories), Zocor® (Merck & Co., Inc.), Halcion® (Pharmacia), Versed® (Roche Pharmaceuticals), Cardioquin® (The Purdue Frederick Company), Quinaglute® (Berlex Laboratories), Quinidex® (A.H. Robins), TikosynTM (Pfizer, Inc.), Propulsid® (Janssen Pharmaceutica Products, L.P.), Orlaam® (Roxane Laboratories), Migranal® (Xcel Pharmaceuticals), Ergonovine (PDRX Pharmaceuticals), Cafergot® (Novartis Pharmaceuticals Corporation), Methergine® (Novartis Pharmaceuticals Corporation) and Orap® (Gate Pharmaceuticals)

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Sandoz Inc.

Princeton, NJ 08540

OS7722, Rev. 06/08

and

OS8359, Rev. 05/08

MF0550REV05/08

Itraconazole Capsules, 100 mg x 30 Capsules - Label

NDC 0185-0550-30

Itraconazole Capsules

100 mg

PHARMACIST: Please dispense with Patient Information.

Rx only

30 Capsules

Sandoz

Itraconazole 100 mg x 30 Capsules - Label

Itraconazole Capsules, 100 mg x 4 Capsules - Blister Card

Lot : ###### EXP: MM/YY

Itraconazole Capsules

100 mg

A.M.

Take two capsules with a meal in the morning.

N (01) 0 03 0185-0550-90 6

Sandoz

Store at 20°-25°C (68°-77°F) [see USP Controlled Room Temperature]. Protect from light and moisture.

Lot : ###### EXP: MM/YY

Itraconazole Capsules

100 mg

P.M.

Take two capsules with a meal in the morning.

N (01) 0 03 0185-0550-90 6

Itraconazole Blister Card

Itraconazole Capsules, 100 mg - Carton

NDC 0185-0550-83

Itraconazole Capsules

100 mg

Rx only

28 Capsules

7-Day Treatment Pack

- 7 days of treatment

- Information guide

Sandoz

Itraconazole Capsules - Carton


ITRACONAZOLE 
itraconazole   capsule
Product Information
Product TypeHUMAN PRESCRIPTION DRUGNDC Product Code (Source)0185-0550
Route of AdministrationCUTANEOUS, ORALDEA Schedule    
Active Ingredient/Active Moiety
Ingredient NameBasis of StrengthStrength
ITRACONAZOLE (ITRACONAZOLE) ITRACONAZOLE100 mg
Inactive Ingredients
Ingredient NameStrength
STARCH, CORN 
D&C YELLOW NO. 10 
FD&C BLUE NO. 1 
FD&C BLUE NO. 2 
FD&C RED NO. 40 
GELATIN 
HYPROMELLOSE 
FERROSOFERRIC OXIDE 
POLYETHYLENE GLYCOL 
TITANIUM DIOXIDE 
Product Characteristics
ColorTURQUOISE (aqua blue opaque cap, light blue clear body) Score no score
ShapeCAPSULESize31mm
FlavorImprint Code E550
Contains    
Packaging
#NDCPackage DescriptionMultilevel Packaging
10185-0550-05500 CAPSULE In 1 BOTTLENone
20185-0550-2828 CAPSULE In 1 BOTTLENone
30185-0550-3030 CAPSULE In 1 BOTTLENone
40185-0550-01100 CAPSULE In 1 BOTTLENone
50185-0550-837 BLISTER PACK In 1 CARTONcontains a BLISTER PACK (0185-0550-90)
50185-0550-904 CAPSULE In 1 BLISTER PACKThis package is contained within the CARTON (0185-0550-83)

Marketing Information
Marketing CategoryApplication Number or Monograph CitationMarketing Start DateMarketing End Date
ANDAANDA07610505/28/2004

Labeler - Sandoz Inc (614842560)
Establishment
NameAddressID/FEIOperations
Sandoz Inc614842560RELABEL, REPACK, MANUFACTURE, ANALYSIS
Establishment
NameAddressID/FEIOperations
Catalent Pharma Solutions, LLC806746405MANUFACTURE
Revised: 02/2010Sandoz Inc