NDC 0378-5100 Itraconazole

Itraconazole

NDC Product Code 0378-5100

NDC 0378-5100-93

Package Description: 30 CAPSULE in 1 BOTTLE, PLASTIC

Price per Unit: $1.18532 per EA

NDC Product Information

Itraconazole with NDC 0378-5100 is a a human prescription drug product labeled by Mylan Pharmaceuticals Inc.. The generic name of Itraconazole is itraconazole. The product's dosage form is capsule and is administered via oral form. The RxNorm Crosswalk for this NDC code indicates a single RxCUI concept is associated to this product: 311204.

Dosage Form: Capsule - A solid oral dosage form consisting of a shell and a filling. The shell is composed of a single sealed enclosure, or two halves that fit together and which are sometimes sealed with a band. Capsule shells may be made from gelatin, starch, or cellulose, or other suitable materials, may be soft or hard, and are filled with solid or liquid ingredients that can be poured or squeezed.

Product Type: Human Prescription Drug What kind of product is this?
Indicates the type of product, such as Human Prescription Drug or Human Over the Counter Drug. This data element matches the “Document Type” field of the Structured Product Listing.

Itraconazole Active Ingredient(s)

What is the Active Ingredient(s) List?
This is the active ingredient list. Each ingredient name is the preferred term of the UNII code submitted.


Inactive Ingredient(s)

About the Inactive Ingredient(s)
The inactive ingredients are all the component of a medicinal product OTHER than the active ingredient(s). The acronym "UNII" stands for “Unique Ingredient Identifier” and is used to identify each inactive ingredient present in a product.

  • FERROSOFERRIC OXIDE (UNII: XM0M87F357)
  • FD&C BLUE NO. 2 (UNII: L06K8R7DQK)
  • GELATIN, UNSPECIFIED (UNII: 2G86QN327L)
  • HYPROMELLOSE, UNSPECIFIED (UNII: 3NXW29V3WO)
  • POLYETHYLENE GLYCOL, UNSPECIFIED (UNII: 3WJQ0SDW1A)
  • POVIDONE, UNSPECIFIED (UNII: FZ989GH94E)
  • PROPYLENE GLYCOL (UNII: 6DC9Q167V3)
  • FERRIC OXIDE RED (UNII: 1K09F3G675)
  • SHELLAC (UNII: 46N107B71O)
  • SODIUM HYDROXIDE (UNII: 55X04QC32I)
  • STARCH, CORN (UNII: O8232NY3SJ)
  • SUCROSE (UNII: C151H8M554)
  • TALC (UNII: 7SEV7J4R1U)
  • TITANIUM DIOXIDE (UNII: 15FIX9V2JP)
  • FERRIC OXIDE YELLOW (UNII: EX438O2MRT)

Administration Route(s)

What are the Administration Route(s)?
The translation of the route code submitted by the firm, indicating route of administration.

  • Oral - Administration to or by way of the mouth.

Pharmacological Class(es)

What is a Pharmacological Class?
These are the reported pharmacological class categories corresponding to the SubstanceNames listed above.

  • Azole Antifungal - [EPC] (Established Pharmacologic Class)
  • Azoles - [CS]
  • Cytochrome P450 3A4 Inhibitors - [MoA] (Mechanism of Action)
  • P-Glycoprotein Inhibitors - [MoA] (Mechanism of Action)
  • Breast Cancer Resistance Protein Inhibitors - [MoA] (Mechanism of Action)

Product Labeler Information

What is the Labeler Name?
Name of Company corresponding to the labeler code segment of the Product NDC.

Labeler Name: Mylan Pharmaceuticals Inc.
Labeler Code: 0378
FDA Application Number: ANDA200463 What is the FDA Application Number?
This corresponds to the NDA, ANDA, or BLA number reported by the labeler for products which have the corresponding Marketing Category designated. If the designated Marketing Category is OTC Monograph Final or OTC Monograph Not Final, then the Application number will be the CFR citation corresponding to the appropriate Monograph (e.g. “part 341”). For unapproved drugs, this field will be null.

Marketing Category: ANDA - A product marketed under an approved Abbreviated New Drug Application. What is the Marketing Category?
Product types are broken down into several potential Marketing Categories, such as NDA/ANDA/BLA, OTC Monograph, or Unapproved Drug. One and only one Marketing Category may be chosen for a product, not all marketing categories are available to all product types. Currently, only final marketed product categories are included. The complete list of codes and translations can be found at www.fda.gov/edrls under Structured Product Labeling Resources.

Start Marketing Date: 07-26-2012 What is the Start Marketing Date?
This is the date that the labeler indicates was the start of its marketing of the drug product.

Listing Expiration Date: 12-31-2021 What is the Listing Expiration Date?
This is the date when the listing record will expire if not updated or certified by the product labeler.

Exclude Flag: N - NO What is the NDC Exclude Flag?
This field indicates whether the product has been removed/excluded from the NDC Directory for failure to respond to FDA"s requests for correction to deficient or non-compliant submissions ("Y"), or because the listing certification is expired ("E"), or because the listing data was inactivated by FDA ("I"). Values = "Y", "N", "E", or "I".

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Information for Patients

Itraconazole

Itraconazole is pronounced as (it'' ra kon' a zole)

Why is itraconazole medication prescribed?
Itraconazole capsules are used to treat fungal infections in the lungs that can spread throughout the body. Itraconazole capsules are also used to treat fungal infections...
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* Please review the disclaimer below.

Itraconazole Product Labeling Information

The product labeling information includes all published material associated to a drug. Product labeling documents include information like generic names, active ingredients, ingredient strength dosage, routes of administration, appearance, usage, warnings, inactive ingredients, etc.

Product Labeling Index

Boxed Warning

Congestive Heart Failure, Cardiac Effects and Drug Interactions: 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 CONTRAINDICATIONS, WARNINGS, PRECAUTIONS: Drug Interactions, ADVERSE REACTIONS: Post-marketing Experience, and CLINICAL PHARMACOLOGY: Special Populations for more information.)Drug Interactions: Coadministration of the following drugs are contraindicated with itraconazole capsules: methadone, disopyramide, dofetilide, dronedarone, quinidine, isavuconazole, ergot alkaloids (such as dihydroergotamine, ergometrine (ergonovine), ergotamine, methylergometrine (methylergonovine)), irinotecan, lurasidone, oral midazolam, pimozide, triazolam, felodipine, nisoldipine, ivabradine, ranolazine, eplerenone, cisapride, naloxegol, lomitapide, lovastatin, simvastatin, avanafil, ticagrelor. In addition, coadministration with colchicine, fesoterodine and solifenacin is contraindicated in subjects with varying degrees of renal or hepatic impairment, and coadministration with eliglustat is contraindicated in subjects that are poor or intermediate metabolizers of CYP2D6 and in subjects taking strong or moderate CYP2D6 inhibitors. See PRECAUTIONS: Drug Interactions section for specific examples. Coadministration with itraconazole can cause elevated plasma concentrations of these drugs and may increase or prolong both the pharmacologic effects and/or adverse reactions to these drugs. For example, increased plasma concentrations of some of these drugs can lead to QT prolongation and ventricular tachyarrhythmias including occurrences of torsades de pointes, a potentially fatal arrhythmia. See CONTRAINDICATIONS and WARNINGS sections, and PRECAUTIONS: Drug Interactions section for specific examples.

Description

Itraconazole capsules are an azole 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:4-[4-[4-[4-[[cis-2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]piperazin-1-yl] phenyl]-2-[(1RS)-1-methylpropyl]-2,4-dihydro-3H-1,2,4-triazol-3-oneItraconazole has a molecular formula of C35H38Cl2N8O4 and a molecular weight of 706. It is a white or almost white powder. It is insoluble in water, very slightly soluble in alcohols, and freely soluble in dichloromethane. It has a pKa of 3.70 (based on extrapolation of values obtained from methanolic solutions) and a log (n-octanol/water) partition coefficient of 5.66 at pH 8.1.Itraconazole capsules contain 100 mg of itraconazole, USP coated on sugar spheres. Inactive ingredients are black iron oxide, FD&C Blue No. 2, gelatin, hypromellose, polyethylene glycol, red iron oxide, sugar spheres, talc, titanium dioxide, and yellow iron oxide. The white printing ink contains povidone, propylene glycol, shellac, sodium hydroxide, and titanium dioxide.

General Pharmacokinetic Characteristics

Peak plasma concentrations of itraconazole are reached within 2 to 5 hours following oral administration. As a consequence of non-linear pharmacokinetics, itraconazole accumulates in plasma during multiple dosing. Steady-state concentrations are generally reached within about 15 days, with Cmax values of 0.5 µg/ml, 1.1 µg/ml and 2 µg/ml after oral administration of 100 mg once daily, 200 mg once daily and 200 mg b.i.d., respectively. The terminal half-life of itraconazole generally ranges from 16 to 28 hours after single dose and increases to 34 to 42 hours with repeated dosing. Once treatment is stopped, itraconazole plasma concentrations decrease to an almost undetectable concentration within 7 to 14 days, depending on the dose and duration of treatment. Itraconazole mean total plasma clearance following intravenous administration is 278 ml/min. Itraconazole clearance decreases at higher doses due to saturable hepatic metabolism.

Absorption

Itraconazole is rapidly absorbed after oral administration. Peak plasma concentrations of itraconazole are reached within 2 to 5 hours following an oral capsule dose. The observed absolute oral bioavailability of itraconazole is about 55%.The oral bioavailability of itraconazole is maximal when itraconazole capsules are taken immediately after a full meal. Absorption of itraconazole capsules is reduced in subjects with reduced gastric acidity, such as subjects taking medications known as gastric acid secretion suppressors (e.g., H2-receptor antagonists, proton pump inhibitors) or subjects with achlorhydria caused by certain diseases. (See PRECAUTIONS: Drug Interactions.) Absorption of itraconazole under fasted conditions in these subjects is increased when itraconazole capsules are administered with an acidic beverage (such as a non-diet cola). When itraconazole capsules were administered as a single 200-mg dose under fasted conditions with non-diet cola after ranitidine pretreatment, a H2-receptor antagonist, itraconazole absorption was comparable to that observed when itraconazole capsules were administered alone. (See PRECAUTIONS: Drug Interactions.)Itraconazole exposure is lower with the capsule formulation than with the oral solution when the same dose of drug is given. (See WARNINGS.)

Distribution

Most of the itraconazole in plasma is bound to protein (99.8%), with albumin being the main binding component (99.6% for the hydroxy-metabolite). It has also a marked affinity for lipids. Only 0.2% of the itraconazole in plasma is present as free drug. Itraconazole is distributed in a large apparent volume in the body (> 700 L), suggesting extensive distribution into tissues. Concentrations in lung, kidney, liver, bone, stomach, spleen and muscle were found to be two to three times higher than corresponding concentrations in plasma, and the uptake into keratinous tissues, skin in particular, up to four times higher. Concentrations in the cerebrospinal fluid are much lower than in plasma.

Metabolism

Itraconazole is extensively metabolized by the liver into a large number of metabolites. In vitro studies have shown that CYP3A4 is the major enzyme involved in the metabolism of itraconazole. The main metabolite is hydroxy-itraconazole, which has in vitro antifungal activity comparable to itraconazole; trough plasma concentrations of this metabolite are about twice those of itraconazole.

Excretion

Itraconazole is excreted mainly as inactive metabolites in urine (35%) and in feces (54%) within 1 week of an oral solution dose. Renal excretion of itraconazole and the active metabolite hydroxy-itraconazole account for less than 1% of an intravenous dose. Based on an oral radiolabeled dose, fecal excretion of unchanged drug ranges from 3% to 18% of the dose. As re-distribution of itraconazole from keratinous tissues appears to be negligible, elimination of itraconazole from these tissues is related to epidermal regeneration. Contrary to plasma, the concentration in skin persists for 2 to 4 weeks after discontinuation of a 4-week treatment and in nail keratin – where itraconazole can be detected as early as 1 week after start of treatment – for at least 6 months after the end of a 3-month treatment period.

Renal Impairment

Limited data are available on the use of oral itraconazole in patients with renal impairment. A pharmacokinetic study using a single 200-mg oral dose of itraconazole 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 x 1.73 m2, the exposure, based on AUC, 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 AUC0-8h). Plasma concentration-versus-time profiles showed wide intersubject variation in all three groups. After a single intravenous dose, the mean terminal half-lives of itraconazole in patients with mild (defined in this study as CrCl 50-79 mL/min), moderate (defined in this study as CrCl 20-49 mL/min), and severe renal impairment (defined in this study as CrCl < 20 mL/min) were similar to that in healthy subjects (range of means 42-49 hours vs. 48 hours in renally impaired patients and healthy subjects, respectively). Overall exposure to itraconazole, based on AUC, was decreased in patients with moderate and severe renal impairment by approximately 30% and 40%, respectively, as compared with subjects with normal renal function. Data are not available in renally impaired patients during long-term use of itraconazole. Dialysis has no effect on the half-life or clearance of itraconazole or hydroxy-itraconazole. (See PRECAUTIONS and DOSAGE AND ADMINISTRATION.)

Limited data are available on the use of oral itraconazole in patients with renal impairment. The exposure of itraconazole may be lower in some patients with renal impairment. Caution should be exercised when itraconazole is administered in this patient population and dose adjustment may be needed. (See CLINICAL PHARMACOLOGY: Special Populations and DOSAGE AND ADMINISTRATION.)

Hepatic Impairment

Itraconazole is predominantly metabolized in the liver. A pharmacokinetic study was conducted in 6 healthy and 12 cirrhotic subjects who were administered a single 100-mg dose of itraconazole as capsule. A statistically significant reduction in mean Cmax (47%) and a 2-fold increase in the elimination half-life (37 ± 17 hours vs. 16 ± 5 hours) of itraconazole were noted in cirrhotic subjects compared with healthy subjects. However, overall exposure to itraconazole, based on AUC, was similar in cirrhotic patients and in healthy subjects. Data are not available in cirrhotic patients during long-term use of itraconazole. (See CONTRAINDICATIONS, PRECAUTIONS: Drug Interactions and DOSAGE AND ADMINISTRATION.)

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. It is recommended that patients with impaired hepatic function be carefully monitored when taking itraconazole capsules. It is recommended that the prolonged elimination half-life of itraconazole observed in the single oral dose clinical trial with itraconazole capsules in cirrhotic patients be considered when deciding to initiate therapy with other medications metabolized by CYP3A4.In patients with elevated or abnormal liver enzymes or active liver disease, or who have experienced liver toxicity with other drugs, treatment with itraconazole capsules is strongly discouraged unless there is a serious or life-threatening situation where the expected benefit exceeds the risk. It is recommended that liver function monitoring be done in patients with pre-existing hepatic function abnormalities or those who have experienced liver toxicity with other medications. (See CLINICAL PHARMACOLOGY: Special Populations and DOSAGE AND ADMINISTRATION.)

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 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 capsules should be discontinued. (See BOXED WARNING, CONTRAINDICATIONS, WARNINGS, PRECAUTIONS: Drug Interactions and ADVERSE REACTIONS: Post-marketing Experience for more information.)

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 Clinical Infections

Itraconazole exhibits in vitro activity against Blastomyces dermatitidis, Histoplasma capsulatum, Histoplasma duboisii, Aspergillus flavus, Aspergillus fumigatus, and Trichophyton species (see INDICATIONS AND USAGE: Description of Clinical Studies). Correlation between minimum inhibitory concentration (MIC) results in vitro and clinical outcome has yet to be established for azole antifungal agents.

Drug Resistance

Isolates from several fungal species with decreased susceptibility to itraconazole have been isolated in vitro and from patients receiving prolonged therapy. Itraconazole is not active against Zygomycetes (e.g., Rhizopus spp., Rhizomucor spp., Mucor spp. and Absidia spp.), Fusarium spp., Scedosporium spp. and Scopulariopsis spp.

Cross-Resistance

Several in vitro studies have reported that some fungal clinical isolates 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. 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 extrapulmonary2.Histoplasmosis, including chronic cavitary pulmonary disease and disseminated, non-meningeal histoplasmosis, and3.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), and2.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.)

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 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 of 200 mg of itraconazole capsules b.i.d., followed by a 3-week period without itraconazole capsules, which was followed by a second 1-week course 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.

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 BOXED WARNING, WARNINGS, PRECAUTIONS: Drug Interactions: Calcium Channel Blockers, ADVERSE REACTIONS: Post-marketing Experience, and CLINICAL PHARMACOLOGY: Special Populations.)

Drug Interactions

Coadministration of a number of CYP3A4 substrates are contraindicated with itraconazole capsules. Plasma concentrations increase for the following drugs: levacetylmethadol (levomethadyl), methadone, disopyramide, dofetilide, dronedarone, quinidine, isavuconazole, ergot alkaloids (such as dihydroergotamine, ergometrine (ergonovine), ergotamine, methylergometrine (methylergonovine)), irinotecan, lurasidone, oral midazolam, pimozide, triazolam, felodipine, nisoldipine, ivabradine, ranolazine, eplerenone, cisapride, naloxegol, lomitapide, lovastatin, simvastatin, avanafil, ticagrelor. In addition, coadministration with colchicine, fesoterodine and solifenacin is contraindicated in subjects with varying degrees of renal or hepatic impairment, and coadministration with eliglustat is contraindicated in subjects that are poor or intermediate metabolizers of CYP2D6 and in subjects taking strong or moderate CYP2D6 inhibitors. (See PRECAUTIONS: Drug Interactions section for specific examples.) This increase in drug concentrations caused by coadministration with itraconazole may increase or prolong both the pharmacologic effects and/or adverse reactions to these drugs. For example, increased plasma concentrations of some of these drugs can lead to QT prolongation and ventricular tachyarrhythmias including occurrences of torsade de pointes, a potentially fatal arrhythmia. Specific examples are listed in PRECAUTIONS: Drug Interactions.Itraconazole capsules should not be administered for the treatment of onychomycosis to pregnant patients or to women contemplating pregnancy.Itraconazole capsules are contraindicated for patients who have shown hypersensitivity to itraconazole. There is limited information regarding cross-hypersensitivity between itraconazole and other azole antifungal agents. Caution should be used when prescribing itraconazole capsules to patients with hypersensitivity to other azoles.

Hepatic Effects

Itraconazole capsules have 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 capsule use or reinstitution of treatment with itraconazole capsules 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 drugs such as cisapride, pimozide, methadone, or quinidine concomitantly with itraconazole capsules and/or other CYP3A4 inhibitors. Concomitant administration of these drugs with itraconazole capsules is contraindicated. (See BOXED WARNING, CONTRAINDICATIONS, and PRECAUTIONS: Drug Interactions.)

Cardiac 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 capsule 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.Itraconazole has been shown to have a negative inotropic effect. When itraconazole was administered intravenously to anesthetized dogs, a dose-related negative inotropic effect was documented. In a healthy volunteer study of itraconazole 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 capsules have 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 although there were also cases reported among those receiving lower total daily doses. 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 coadministering itraconazole and calcium channel blockers due to an increased risk of CHF. Concomitant administration of itraconazole capsules and felodipine or 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.)

Interaction Potential

Itraconazole capsules have a potential for clinically important drug interactions. Coadministration of specific drugs with itraconazole may result in changes in efficacy of itraconazole and/or the coadministered drug, life-threatening effects and/or sudden death. Drugs that are contraindicated, not recommended or recommended for use with caution in combination with itraconazole are listed in PRECAUTIONS: Drug Interactions.

Interchangeability

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.

General

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 non-diet 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.)

Hepatotoxicity

Rare cases of serious hepatotoxicity have been observed with itraconazole capsule treatment, including some cases within the first week. It is recommended that liver function monitoring be considered in all patients receiving itraconazole capsules. Treatment should be stopped immediately and liver function testing should be conducted in patients who develop signs and symptoms suggestive of liver dysfunction.

Neuropathy

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

Cystic Fibrosis

If a cystic fibrosis patient does not respond to itraconazole capsules, consideration should be given to switching to alternative therapy. For more information concerning the use of itraconazole in cystic fibrosis patients see the prescribing information for itraconazole oral solution.

Hearing Loss

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 BOXED WARNING: Drug Interactions, CONTRAINDICATIONS: Drug Interactions and PRECAUTIONS: Drug Interactions). The hearing loss usually resolves when treatment is stopped, but can persist in some patients.

Information For Patients

  • •The topical effects of mucosal exposure may be different between the itraconazole capsules and oral solution. Only the oral solution has been demonstrated effective for oral and/or esophageal candidiasis. Itraconazole capsules should not be used interchangeably with itraconazole oral solution. •Instruct patients to take itraconazole capsules with a full meal. Itraconazole capsules must be swallowed whole. •Instruct patients about the signs and symptoms of congestive heart failure, and if these signs or symptoms occur during itraconazole capsule administration, they should discontinue itraconazole capsules and contact their healthcare provider immediately. •Instruct patients to stop itraconazole capsule treatment immediately and contact their healthcare provider if any signs and symptoms suggestive of liver dysfunction develop. Such signs and symptoms may include unusual fatigue, anorexia, nausea and/or vomiting, jaundice, dark urine, or pale stools. •Instruct patients to contact their physician before taking any concomitant medications with itraconazole to ensure there are no potential drug interactions. •Instruct patients that hearing loss can occur with the use of itraconazole. The hearing loss usually resolves when treatment is stopped, but can persist in some patients. Advise patients to discontinue therapy and inform their physicians if any hearing loss symptoms occur. •Instruct patients that dizziness or blurred/double vision can sometimes occur with itraconazole. Advise patients that if they experience these events, they should not drive or use machines.

Effect Of Itraconazole Capsules On Other Drugs

Itraconazole and its major metabolite, hydroxy-itraconazole, are potent CYP3A4 inhibitors. Itraconazole is an inhibitor of the drug transporters P-glycoprotein and breast cancer resistance protein (BCRP). Consequently, itraconazole capsules have the potential to interact with many concomitant drugs resulting in either increased or sometimes decreased concentrations of the concomitant drugs. Increased concentrations may increase the risk of adverse reactions associated with the concomitant drug which can be severe or life-threatening in some cases (e.g., QT prolongation, Torsades de Pointes, respiratory depression, hepatic adverse reactions, hypersensitivity reactions, myelosuppression, hypotension, seizures, angioedema, atrial fibrillation, bradycardia, priapism). Reduced concentrations of concomitant drugs may reduce their efficacy. Table 1 lists examples of drugs that may have their concentrations affected by itraconazole, but is not a comprehensive list. Refer to the approved product labeling to become familiar with the interaction pathways, risk potential, and specific actions to be taken with regards to each concomitant drug prior to initiating therapy with itraconazole capsules.Although many of the clinical drug interactions in Table 1 are based on information with a similar azole antifungal, ketoconazole, these interactions are expected to occur with itraconazole capsules.Table 1. Drug Interactions with Itraconazole Capsules that Affect Concomitant Drug ConcentrationsConcomitant Drug Within ClassPrevention or ManagementDrug Interactions with Itraconazole Capsules that Increase Concomitant Drug Concentrations and May Increase Risk of Adverse Reactions Associated with the Concomitant DrugAlpha BlockersAlfuzosinSilodosinTamsulosinNot recommended during and 2 weeks after itraconazole capsule treatment.AnalgesicsMethadoneContraindicated during and 2 weeks after itraconazole capsule treatment.FentanylNot recommended during and 2 weeks after itraconazole capsule treatment.AlfentanilBuprenorphine (IV and sublingual)OxycodoneBased on clinical drug interaction formulation with itraconazole.SufentanilMonitor for adverse reactions. Concomitant drug dose reduction may be necessary.AntiarrhythmicsDisopyramideDofetilideDronedaroneQuinidineContraindicated during and 2 weeks after itraconazole capsule treatment.DigoxinMonitor for adverse reactions. Concomitant drug dose reduction may be necessary.AntibacterialsBedaquilineBased on 400 mg Bedaquiline once daily for 2 weeks.Concomitant itraconazole capsules not recommended for more than 2 weeks at any time during bedaquiline treatment.RifabutinNot recommended 2 weeks before, during, and 2 weeks after itraconazole capsule treatment. See also Table 2.ClarithromycinMonitor for adverse reactions. Concomitant drug dose reduction may be necessary. See also Table 2.TrimetrexateMonitor for adverse reactions. Concomitant drug dose reduction may be necessary.Anticoagulants and AntiplateletsTicagrelorContraindicated during and 2 weeks after itraconazole capsule treatment.ApixabanRivaroxabanVorapaxarNot recommended during and 2 weeks after itraconazole capsule treatment.CilostazolDabigatranWarfarinMonitor for adverse reactions. Concomitant drug dose reduction may be necessary.AnticonvulsantsCarbamazepineNot recommended 2 weeks before, during, and 2 weeks after itraconazole capsule treatment. See also Table 2.Antidiabetic DrugsRepaglinideSaxagliptinMonitor for adverse reactions. Concomitant drug dose reduction may be necessary.Antihelminthics, Antifungals and AntiprotozoalsIsavuconazoniumContraindicated during and 2 weeks after itraconazole capsule treatment.PraziquantelMonitor for adverse reactions. Concomitant drug dose reduction may be necessary.Artemether-lumefantrineQuinineMonitor for adverse reactions.Antimigraine DrugsErgot alkaloids (e.g., dihydroergotamine, ergotamineContraindicated during and 2 weeks after itraconazole capsule treatment.EletriptanMonitor for adverse reactions. Concomitant drug dose reduction may be necessary.AntineoplasticsIrinotecanContraindicated during and 2 weeks after itraconazole capsule treatment.AxitinibBosutinibCabazitaxelCabozantinibCeritinibCobimetinibCrizotinibDabrafenibDasatinibDocetaxelIbrutinibLapatinibNilotinibOlaparibPazopanibSunitinibTrabectedinTrastuzumab-emtansineVinca alkaloidsNot recommended during and 2 weeks after itraconazole capsule treatment.Bortezomib Brentuximab-vedotinBusulfanErlotinibGefitinibIdelalisib ImatinibIxabepiloneNintedanibPanobinostatPonatinibRuxolitinibSonidegibVandetanibMonitor for adverse reactions. Concomitant drug dose reduction may be necessary. For idelalisib, see also Table 2.Antipsychotics, Anxiolytics and HypnoticsAlprazolam Aripiprazole Buspirone Diazepam HaloperidolMidazolam (IV) QuetiapineRamelteonRisperidoneSuvorexantMonitor for adverse reactions. Concomitant drug dose reduction may be necessary.ZopicloneMonitor for adverse reactions. Concomitant drug dose reduction may be necessary.LurasidoneMidazolam (oral)PimozideTriazolamContraindicated during and 2 weeks after itraconazole capsule treatment.AntiviralsSimeprevirNot recommended during and 2 weeks after itraconazole capsule treatment.DaclatasvirIndinavirMaravirocMonitor for adverse reactions. Concomitant drug dose reduction may be necessary. For indinavir, see also Table 2.CobicistatElvitegravir (ritonavir-boosted)RitonavirSaquinavir (unboosted)Monitor for adverse reactions. See also Table 2.Tenofovir disoproxil fumarateMonitor for adverse reactions.Beta BlockersNadololMonitor for adverse reactions. Concomitant drug dose reduction may be necessary.Calcium Channel BlockersFelodipineNisoldipineContraindicated during and 2 weeks after itraconazole capsule treatment.DiltiazemOther dihydropyridinesVerapamilMonitor for adverse reactions. Concomitant drug dose reduction may be necessary. For diltiazem, see also Table 2.Cardiovascular Drugs, MiscellaneousIvabradineRanolazineContraindicated during and 2 weeks after itraconazole capsule treatment.AliskirenRiociguatSildenafil (for pulmonary hypertension)Tadalafil (for pulmonary hypertension)Not recommended during and 2 weeks after itraconazole capsule treatment. For sildenafil and tadalafil, see also Urologic Drugs below.BosentanGuanfacineMonitor for adverse reactions. Concomitant drug dose reduction may be necessary.ContraceptivesDienogestUlipristalMonitor for adverse reactions.DiureticsEplerenoneContraindicated during and 2 weeks after itraconazole capsule treatment.Gastrointestinal DrugsCisaprideNaloxegolContraindicated during and 2 weeks after itraconazole capsule treatment.AprepitantLoperamideMonitor for adverse reactions. Concomitant drug dose reduction may be necessary.NetupitantMonitor for adverse reactions.ImmunosuppressantsEverolimusSirolimusTemsirolimus (IV)Not recommended during and 2 weeks after itraconazole capsule treatment.Budesonide (inhalation)Budesonide (noninhalation)Ciclesonide (inhalation)Cyclosporine (IV)Cyclosporine (non-IV)DexamethasoneaFluticasone (inhalation)Fluticasone (nasal)MethylprednisoloneTacrolimus (IV)Tacrolimus (oral)Monitor for adverse reactions. Concomitant drug dose reduction may be necessary.Lipid-Lowering DrugsLomitapideLovastatinSimvastatinContraindicated during and 2 weeks after itraconazole capsule treatment.AtorvastatinMonitor for drug adverse reactions. Concomitant drug dose reduction may be necessary.Respiratory DrugsSalmeterolNot recommended during and 2 weeks after itraconazole capsule treatment.SSRIs, Tricyclics and Related AntidepressantsVenlafaxineMonitor for adverse reactions. Concomitant drug dose reduction may be necessary.Urologic DrugsAvanafilContraindicated during and 2 weeks after itraconazole capsule treatment.FesoterodinePatients with moderate to severe renal or hepatic impairment: Contraindicated during and 2 weeks after itraconazole capsule treatment.Other patients: Monitor for adverse reactions. Concomitant drug dose reduction may be necessary.SolifenacinPatients with severe renal or moderate to severe hepatic impairment: Contraindicated during and 2 weeks after itraconazole capsule treatment.Other patients: Monitor for adverse reactions. Concomitant drug dose reduction may be necessary.DarifenacinVardenafilNot recommended during and 2 weeks after itraconazole capsule treatment. DutasterideOxybutyninSildenafil (for erectile dysfunction)Tadalafil (for erectile dysfunction and benign prostatic hyperplasia)TolterodineMonitor for adverse reactions. Concomitant drug dose reduction may be necessary. For sildenafil and tadalafil, see also Cardiovascular Drugs above.Miscellaneous Drugs and Other SubstancesColchicinePatients with renal or hepatic impairment: Contraindicated during and 2 weeks after itraconazole capsule treatment.Other patients: Not recommended during and 2 weeks after itraconazole capsule treatment.EliglustatCYP2D6 EMsEMs: extensive metabolizers; IMs: intermediate metabolizers; PMs: poor metabolizers taking a strong or moderate CYP2D6 inhibitor, CYP2D6 IMs, or CYP2D6 PMs: Contraindicated during and 2 weeks after itraconazole capsule treatment. CYP2D6 EMs not taking a strong or moderate CYP2D6 inhibitor: Monitor for adverse reactions. Eliglustat dose reduction may be necessary.Lumacaftor/IvacaftorNot recommended 2 weeks before, during and 2 weeks after itraconazole capsule treatment.Alitretinoin (oral)CabergolineCannabinoidsCinacalcetIvacaftorMonitor for adverse reactions. Concomitant drug dose reduction may be necessary.Vasopressin Receptor AntagonistsConivaptanTolvaptanNot recommended during and 2 weeks after itraconazole capsule treatment.Drug Interactions with Itraconazole Capsules that Decrease Concomitant Drug Concentrations and May Reduce Efficacy of the Concomitant DrugAntineoplasticsRegorafenibNot recommended during and 2 weeks after itraconazole capsule treatment.Gastrointestinal DrugsSacchromyces boulardiiNot recommended during and 2 weeks after itraconazole capsule treatment.Nonsteroidal Anti-Inflammatory DrugsMeloxicamConcomitant drug dose increase may be necessary.

Effect Of Other Drugs On Itraconazole Capsules

Itraconazole is mainly metabolized through CYP3A4. Other substances that either share this metabolic pathway or modify CYP3A4 activity may influence the pharmacokinetics of itraconazole. Some concomitant drugs have the potential to interact with itraconazole resulting in either increased or sometimes decreased concentrations of itraconazole. Increased concentrations may increase the risk of adverse reactions associated with itraconazole capsules. Decreased concentrations may reduce itraconazole capsule efficacy.Table 2 lists examples of drugs that may affect itraconazole concentrations, but is not a comprehensive list. Refer to the approved product labeling to become familiar with the interaction pathways, risk potential and specific actions to be taken with regards to each concomitant drug prior to initiating therapy with itraconazole capsules.Although many of the clinical drug interactions in Table 2 are based on information with a similar azole antifungal, ketoconazole, these interactions are expected to occur with itraconazole.Table 2. Drug Interactions with Other Drugs that Affect Itraconazole ConcentrationsConcomitant Drug Within ClassPrevention or ManagementDrug Interactions with Other Drugs that Increase Itraconazole Concentrations and May Increase the Risk of Adverse Reactions Associated with ItraconazoleAntibacterialsCiprofloxacinBased on clinical drug interaction information with itraconazoleErythromycinClarithromycinMonitor for adverse reactions. Itraconazole capsule dose reduction may be necessary.AntineoplasticsIdelalisibMonitor for adverse reactions. Itraconazole capsule dose reduction may be necessary. See also Table 1.AntiviralsCobicistatDarunavir (ritonavir-boosted)Elvitegravir (ritonavir-boosted)Fosamprenavir (ritonavir-boosted)IndinavirRitonavirSaquinavirMonitor for adverse reactions. Itraconazole capsule dose reduction may be necessary. For cobicistat, elvitegravir, indinavir, ritonavir, and saquinavir, see also Table 1.Calcium Channel BlockersDiltiazemMonitor for adverse reactions. Itraconazole capsule dose reduction may be necessary. See also Table 1.Drug Interactions with Other Drugs that Decrease Itraconazole Concentrations and May Reduce Efficacy of ItraconazoleAntibacterialsIsoniazidRifampicinNot recommended 2 weeks before and during itraconazole capsule treatment.RifabutinNot recommended 2 weeks before, during, and 2 weeks after itraconazole capsule treatment. See also Table 1.AnticonvulsantsPhenobarbitalPhenytoinNot recommended 2 weeks before and during itraconazole capsule treatment.CarbamazepineNot recommended 2 weeks before, during, and 2 weeks after itraconazole capsule treatment. See also Table 1.AntiviralsEfavirenzNevirapineNot recommended 2 weeks before and during itraconazole capsule treatment.Gastrointestinal DrugsDrugs that reduce gastric acidity e.g., acid neutralizing medicines such as aluminum hydroxide, or acid secretion suppressors such as H2-receptor antagonists and proton pump inhibitors.Use with caution. Administer acid neutralizing medicines at least 2 hours before or 2 hours after the intake of itraconazole capsules.Miscellaneous Drugs and Other SubstancesLumacaftor/IvacaftorNot recommended 2 weeks before, during, and 2 weeks after itraconazole capsule treatment.

Pediatric Population

Interaction studies have only been performed in adults.

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 times the maximum recommended human dose [MRHD]). Male rats treated with 25 mg/kg/day (3.1 times the 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 times the 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 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 times the 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 times the MRHD).

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 40-160 mg/kg/day (5-20 times the MRHD), and in mice at dosage levels of approximately 80 mg/kg/day (10 times the MRHD). Itraconazole has been shown to cross the placenta in a rat model. 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 capsules should be used for the treatment of systemic fungal infections in pregnancy only if the benefit outweighs the potential risk. Itraconazole capsules should not be administered for the treatment of onychomycosis to pregnant patients or to women contemplating pregnancy. Itraconazole capsules 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 capsule 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 capsule 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 capsules have not been established in pediatric patients. 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 times the 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 times the MRHD) over 1 year or 160 mg/kg/day (20 times the MRHD) for 6 months, itraconazole induced small tooth pulp with hypocellular appearance in some rats.

Geriatric Use

Clinical studies of itraconazole capsules did not include sufficient numbers of subjects aged 65 years and over to determine whether they respond differently from younger subjects. It is advised to use itraconazole capsules in these patients only if it is determined that the potential benefit outweighs the potential risks. In general, it is recommended that the dose selection for an elderly patient should be taken into consideration, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.Transient or permanent hearing loss has been reported in elderly patients receiving treatment with itraconazole. Several of these reports included concurrent administration of quinidine which is contraindicated (see BOXED WARNING: Drug Interactions, CONTRAINDICATIONS: Drug Interactions and PRECAUTIONS: Drug Interactions).

Hiv-Infected Patients

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

Adverse Reactions

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.Itraconazole capsules have 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 capsule use should be reassessed. (See WARNINGS: Hepatic Effects and PRECAUTIONS: Hepatotoxicity and 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.Table 3: Clinical Trials of Systemic Fungal Infections: Adverse Events Occurring with an Incidence of Greater than or Equal to 1%Body System/Adverse Event Incidence (%) (N = 602)Gastrointestinal Nausea 11Vomiting 5Diarrhea 3Abdominal Pain 2Anorexia 1Body as a Whole Edema 4Fatigue 3Fever 3Malaise 1Skin and AppendagesRashRash tends to occur more frequently in immunocompromised patients receiving immunosuppressive medications.9Pruritus 3Central/Peripheral Nervous System Headache4Dizziness 2PsychiatricLibido Decreased1Somnolence 1Cardiovascular Hypertension 3Metabolic/NutritionalHypokalemia2Urinary SystemAlbuminuria1Liver and Biliary System Hepatic Function Abnormal3Reproductive System, Male Impotence1Adverse 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.Table 4: Clinical Trials of Onychomycosis of the Toenail: Adverse Events Leading to Temporary or Permanent Discontinuation of TherapyAdverse EventIncidence (%)Itraconazole (N = 112)Elevated Liver Enzymes (greater than twice the upper limit of normal) 4Gastrointestinal Disorders 4Rash 3Hypertension 2Orthostatic Hypotension 1Headache 1Malaise 1Myalgia 1Vasculitis 1Vertigo 1The 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 dosing 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.Table 5: Clinical Trials of Onychomycosis of the Fingernail: Adverse Events Leading to Temporary or Permanent Discontinuation of TherapyAdverse Event Incidence (%)Itraconazole (N = 37)Rash/Pruritus 3Hypertriglyceridemia 3The 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%.

Adverse Events Reported From Other Clinical Trials

In addition, the following adverse drug reaction was reported in patients who participated in itraconazole capsule clinical trials: Hepatobiliary Disorders: hyperbilirubinemia.The following is a list of additional adverse drug reactions associated with itraconazole that have been reported in clinical trials of itraconazole oral solution and itraconazole IV excluding the adverse reaction term “injection site inflammation” which is specific to the injection route of administration:Cardiac Disorders: cardiac failure, left ventricular failure, tachycardia;General Disorders and Administration Site Conditions: face edema, chest pain, chills;Hepatobiliary Disorders: hepatic failure, jaundice;Investigations: alanine aminotransferase increased, aspartate aminotransferase increased, blood alkaline phosphatase increased, blood lactate dehydrogenase increased, blood urea increased, gamma-glutamyltransferase increased, urine analysis abnormal;Metabolism and Nutrition Disorders: hyperglycemia, hyperkalemia, hypomagnesemia;Psychiatric Disorders: confusional state;Renal and Urinary Disorders: renal impairment;Respiratory, Thoracic, and Mediastinal Disorders: dysphonia, cough;Skin and Subcutaneous Tissue Disorders: rash erythematous, hyperhidrosis;Vascular Disorders: hypotension

Post-Marketing Experience

Adverse drug reactions that have been first identified during post-marketing experience with itraconazole (all formulations) are listed in the table below. Because these reactions are reported voluntarily from a population of uncertain size, reliably estimating their frequency or establishing a causal relationship to drug exposure is not always possible.Table 6: Post-marketing Reports of Adverse Drug ReactionsBlood and Lymphatic System Disorders: Leukopenia, neutropenia, thrombocytopenia Immune System Disorders: Anaphylaxis; anaphylactic, anaphylactoid and allergic reactions; serum sickness; angioneurotic edemaNervous System Disorders: Peripheral neuropathy, paresthesia, hypoesthesia, tremorEye Disorders: Visual disturbances, including vision blurred and diplopiaEar and Labyrinth Disorders: Transient or permanent hearing lossCardiac Disorders: Congestive heart failure Respiratory, Thoracic and Mediastinal Disorders:Pulmonary edema, dyspnea Gastrointestinal Disorders: Pancreatitis, dysgeusiaHepatobiliary Disorders: Serious hepatotoxicity (including some cases of fatal acute liver failure), hepatitisSkin and Subcutaneous Tissue Disorders: Toxic epidermal necrolysis, Stevens-Johnson syndrome, acute generalized exanthematous pustulosis, erythema multiforme, exfoliative dermatitis, leukocytoclastic vasculitis, alopecia, photosensitivity, urticariaMusculoskeletal and Connective Tissue Disorders:Arthralgia Renal and Urinary Disorders: Urinary incontinence, pollakiuria Reproductive System and Breast Disorders:Erectile dysfunction General Disorders and Administration Site Conditions:Peripheral edemaInvestigations:Blood creatine phosphokinase increasedThere is limited information on the use of itraconazole capsules 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 capsules has not been established. (See CLINICAL PHARMACOLOGY: Special Populations, CONTRAINDICATIONS, WARNINGS, and PRECAUTIONS: Drug Interactions for more information.)

Overdosage

Itraconazole is not removed by dialysis. In the event of accidental overdosage, supportive measures should be employed. Activated charcoal may be given if considered appropriate. In general, adverse events reported with overdose have been consistent with adverse drug reactions already listed in this package insert for itraconazole. (See ADVERSE REACTIONS.)

Dosage And Administration

Itraconazole capsules should be taken with a full meal to ensure maximal absorption. Itraconazole capsules must be swallowed whole.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 to 400 mg is recommended.

Treatment In Life-Threatening Situations

In life-threatening situations, a loading dose should be used.Although clinical studies did not provide for a loading dose, it is recommended, based on pharmacokinetic data, that a loading dose of 200 mg (2 capsules) three times daily (600 mg/day) be given for the first 3 days of treatment.Treatment should be continued for a minimum of 3 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.

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 courses, each consisting of 200 mg (2 capsules) b.i.d. (400 mg/day) for 1 week. The courses are separated by a 3-week period without itraconazole capsules.

Use In Patients With 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 and PRECAUTIONS.)

Use In Patients With 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, WARNINGS, and PRECAUTIONS.)

How Supplied

Itraconazole Capsules are available containing 100 mg of itraconazole, USP.The 100 mg capsule is a hard-shell gelatin capsule with a dark blue opaque cap and caramel opaque body filled with white to off-white beads. The capsule is axially printed with MYLAN over 5100 in white ink on both the cap and the body. They are available as follows:NDC 0378-5100-93bottles of 30 capsulesStore at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.]Protect from light and moisture.Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure.Keep out of reach of children.

Patient Information

  • Itraconazole Capsules(it″ ra kon′ a zole)This summary contains important information about itraconazole capsules. This information is for patients who have been prescribed itraconazole capsules to treat fungal nail infections. If your doctor prescribed itraconazole capsules 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 capsules are 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 capsules?Itraconazole capsules are used to treat fungal nail infections. However, itraconazole capsules are not for everyone. Do not take itraconazole capsules for fungal nail infections if you have had heart failure, including congestive heart failure. You should not take itraconazole capsules if you are taking certain medicines that could lead to serious or life-threatening medical problems. (See “Who should not take itraconazole capsules?” 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 capsules.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 are itraconazole capsules?Itraconazole capsules are 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 capsules work in children with fungal nail infections or if they are 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. 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 capsules?Itraconazole capsules are not for everyone. Your doctor will decide if itraconazole capsules are the right treatment for you. Some patients should not take itraconazole capsules 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; or if you have cystic fibrosis, or have had an allergic reaction to itraconazole capsules or any other antifungal medicines.Never take itraconazole capsules if you: •have had heart failure, including congestive heart failure. •are taking any of the medicines listed below. Dangerous or even life-threatening side effects could result: •avanafil (such as Stendra™) •cisapride (such as Propulsid®) •colchicine (such as Colcrys™) [if you also have pre-existing kidney or liver impairment] •disopyramide (such as Norpace®) •dofetilide (such as Tikosyn™) •dronedarone (such as Multaq®) •eliglustat (such as Cerdelga™) [if you know you do not break down drugs that are broken down by the enzyme CYP2D6] •eplerenone (such as Inspra®) •ergot alkaloids (such as Migranal®, Ergonovine, Cafergot®, Methergine®) •felodipine (such as Plendil®) •fesoterodine (such as Toviaz®) [if you also have pre-existing kidney or liver impairment] •irinotecan (such as Camptosar®) •isavuconazole (such as Cresemba®) •ivabradine (such as Corlanor®) •lomitapide (such as Juxtapid™) •lovastatin (such as Mevacor®, Advicor®, Altocor™) •lurasidone (such as Latuda®) •methadone (such as Dolophine®) •midazolam (such as Versed®) •naloxegol (such as Movantik®) •nisoldipine (such as Sular®) •pimozide (such as Orap®) •quinidine (such as Cardioquin®, Quinaglute®, Quinidex®) •ranolazine (such as Ranexa®) •simvastatin (such as Zocor®) •solifenacin (such as Vesicare®) [if you also have pre-existing kidney or liver impairment] •ticagrelor (such as Brilinta®) •triazolam (such as Halcion®) •have ever had an allergic reaction to itraconazole. Taking itraconazole capsules with certain other medicines may 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. Your doctor will decide if itraconazole capsules are the right treatment for you.What should I know about itraconazole capsules and pregnancy or breast-feeding?Never take itraconazole capsules 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 capsule 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 capsules.How should I take itraconazole capsules?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 capsules once a day for 12 weeks, or twice a day for 1 week in a dosing schedule. You will receive a bottle of capsules. Do not skip any doses. Be sure to finish all your itraconazole capsules 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 capsules can develop liver problems.Itraconazole capsules can sometimes cause dizziness or blurred/double vision. If you have these symptoms, do not drive or use machines.If you forget to take or miss doses of itraconazole capsules, ask your doctor what you should do with the missed doses. What are the possible side effects of itraconazole capsules?The most common side effects include: headache, and digestive system problems (such as nausea, and abdominal pain).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 capsules 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 capsules 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 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 capsules could develop serious liver problems and these could be warning signs.Stop itraconazole capsules and call your doctor right away if you experience any hearing loss symptoms. In very rare cases, patients taking itraconazole capsules have reported temporary or permanent hearing loss.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, constipation, fever, inflammation of the pancreas, menstrual disorder, erectile dysfunction, dizziness, muscle pain, painful joints, unpleasant taste, or hair loss. These are not all the side effects of itraconazole capsules. Your doctor or pharmacist can give you a more complete list.Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.What should I do if I take an overdose of itraconazole capsules?If you think you took too many itraconazole capsules, 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 capsules, out of the reach of children. Store itraconazole capsules at room temperature in a dry place away from light.General advice about itraconazole capsulesMedicines are sometimes prescribed for conditions that are not mentioned in patient information leaflets. Do not use itraconazole capsules for a condition for which they were not prescribed. Do not give itraconazole capsules to other people, even if they have the same symptoms you have. They may harm them.This leaflet summarizes the most important information about itraconazole capsules. If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for information about itraconazole capsules that is written for health professionals or you can call Mylan Pharmaceuticals Inc. at 1-877-446-3679 (1-877-4-INFO-RX).This patient information has been approved by the U.S. Food and Drug Administration.The brands listed are trademarks of their respective owners.Manufactured for:Mylan Pharmaceuticals Inc.Morgantown, WV 26505 U.S.A.Manufactured by:Mylan Laboratories LimitedHyderabad — 500 096, India75063512Revised: 10/2017MX:ITRA:R8

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