rac-4-[4-[4-[4-[[2-(2,4-ジクロロフェニル)-2α*-(1H-1,2,4-トリアゾール-1-イルメチル)-1,3-ジオキソラン-4α*-イル]メトキシ]フェニル]ピペラジン-1-イル]フェニル]-2,4-ジヒドロ-2-[(R*)-1-メチルプロピル]-3H-1,2,4-トリアゾール-3-オン

Lipophilic: partition coefficient (n-octanol/aqueous buffer pf pH 8.1): 5.66

6.5

Solid

Crystals from toluene

Practically insoluble in water and dilute acidic solutions

9.64e-03 g/L

Breast Feeding; Lactation; Milk, Human; Antifungal Agents

FDA approved drugs -> Active ingredient

FDA approved drugs -> Active ingredient

Antifungal medicines

EMA approved medicines: Veterinary medicine

Active Ingredients (Itraconazole) -> FDA Greenbook

Pharmaceuticals -> UK Veterinary Medicines Directorate List

168-170

166.2 °C

166.2 °C

3.7

pKa = 3.7

Warning

H302 (100%): Harmful if swallowed [Warning Acute toxicity, oral]

P261, P264, P264+P265, P270, P271, P280, P301+P317, P302+P352, P304+P340, P305+P351+P338, P319, P321, P330, P332+P317, P337+P317, P362+P364, P403+P233, P405, and P501 (click each P-code to see the statement)

Aggregated GHS information provided per 88 reports by companies from 7 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

Warning

H302 (100%): Harmful if swallowed [Warning Acute toxicity, oral]

The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies currently marketed prescription drug products, including itraconazole, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.

/Incompatible with/ oxidizing agents.

The manufacturer states that itraconazole injection should not be diluted with 5% dextrose injection or with lactated Ringer's injection, alone or in combination with any other diluent, since information is not available regarding the physical and/or chemical compatibility of itraconazole with these diluents.

Water spray, dry chemical, carbon dioxide or foam as appropriate for surrounding fire and materials.

As with all fires, evacuate personnel to a safe area. Firefighters should use self-contained breathing equipment and protective clothing.

Itraconazole capsules should be stored at a controlled room temperature of 15-25 °C and protected from light and moisture. Itraconazole oral solution should be stored at 25 °C or lower and should not be frozen.

Commercially available itraconazole injection should be stored at 25 °C or lower and protected from light; freezing should be avoided. Following dilution of itraconazole injection in the 0.9% sodium chloride injection diluent supplied by the manufacturer, itraconazole injections may be stored at 2-8 deg or 15-25 °C for up to 48 hours. The injection should be protected from light during storage, but may be exposed to normal room light during administration.

Store in tight, light-resistant container as defined in the USP-NF. This material should be handled and stored per label instructions to ensure product integrity.

Wear approved respiratory protection, chemically compatible gloves and protective clothing. Wipe up spillage or collect spillage using a high-efficiency vacuum cleaner. Avoid breathing dust. Place spillage in appropriately -labelled container for disposal. Wash spill site.

SRP: Expired or waste pharmaceuticals shall carefully take into consideration applicable DEA, EPA, and FDA regulations. It is not appropriate to dispose by flushing the pharmaceutical down the toilet or discarding to trash. If possible return the pharmaceutical to the manufacturer for proper disposal being careful to properly label and securely package the material. Alternatively, the waste pharmaceutical shall be labeled, securely packaged and transported by a state licensed medical waste contractor to dispose by burial in a licensed hazardous or toxic waste landfill or incinerator.

SRP: At the time of review, regulatory criteria for small quantity disposal are subject to significant revision, however, household quantities of waste pharmaceuticals may be managed as follows: Mix with wet cat litter or coffee grounds, double bag in plastic, discard in trash.

SRP: Local exhaust ventilation should be applied wherever there is an incidence of point source emissions or dispersion of regulated contaminants in the work area. Ventilation control of the contaminant as close to its point of generation is both the most economical and safest method to minimize personnel exposure to airborne contaminants. Ensure that the local ventilation moves the contaminant away from the worker.

This material is assumed to be combustible. As with all dry powders it is advisable to ground mechanical equipment in contact with dry material to dissipate the potential buildup of static electricity.

As a general rule, when handling USP Reference Standards avoid all contact and inhalation of dust, mists, and/or vapors associated with the material. Wash thoroughly after handling.

/Wear/ chemically compatible gloves, safety glasses or goggles /and/ protect exposed skin.

Engineering controls such as exhaust ventilation are recommended.

Use a NIOSH-approved respirator, if it is determined to be necessary by an industrial hygiene survey involving air monitoring. In the event that a respirator is not required, an approved dust mask should be used.

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. 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.

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.

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.

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

For more Interactions (Complete) data for Itraconazole (29 total), please visit the HSDB record page.

Transient, mild-to-moderate elevations in serum aminotransferase levels occur in 1% to 5% of patients on itraconazole. These elevations are largely asymptomatic and self-limited, resolving even with continuation of therapy. Clinically apparent hepatotoxicity is rare but has been well described and can be severe and even fatal. The liver injury from itraconazole typically presents 1 to 6 months after starting therapy with symptoms of fatigue and jaundice. The pattern of serum enzyme elevations is typically cholestatic (Case 1), but cases of severe hepatitis with acute liver failure typically have a hepatocellular enzyme pattern (Case 2). Immunoallergic features (rash, fever, eosinophilia) are uncommon as is autoantibody formation. Recovery upon stopping therapy can be delayed for several weeks and generally takes 4 to 10 weeks, although in some cases recovery may be prolonged.

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 6,600(SRC), determined from a log Kow of 5.66(2) and a regression-derived equation(3), indicates that itraconazole is expected to be immobile in soil(SRC). The pKa of itraconazole is 3.7(4), indicating that this compound will exist almost entirely in the cation form in the environment and cations generally adsorb more strongly to soils containing organic carbon and clay than their neutral counterparts(5). Volatilization from moist soil is not expected because the compound exists as a cation and cations do not volatilize. Itraconazole is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 2.6X10-20 mm Hg at 25 °C(SRC), determined from a fragment constant method(6). A biodegradation model indicates persistence on the order of months and longer(7), suggesting that biodegradation is not expected to be an important environmental fate process in soil(SRC).

AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 6,600(SRC), determined from a log Kow of 5.66(2) and a regression-derived equation(3), indicates that itraconazole is expected to adsorb to suspended solids and sediment(SRC). A pKa of 3.7(4) indicates itraconazole will exist almost entirely in the cation form at pH values of 5 to 9 and therefore volatilization from water surfaces is not expected to be an important fate process(SRC). According to a classification scheme(5), an estimated BCF of 2,500(SRC), from its log Kow(2) and a regression-derived equation(3), suggests the potential for bioconcentration in aquatic organisms is very high, provided the compound is not metabolized by the organism(SRC). A biodegradation model indicates persistence on the order of months and longer(6), suggesting that biodegradation is not expected to be an important environmental fate process in water(SRC).

ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), itraconazole, which has an estimated vapor pressure of 2.6X10-20 mm Hg at 25 °C(SRC), determined from a fragment constant method(2), is expected to exist solely in the particulate phase in the ambient atmosphere. Particulate-phase itraconazole may be removed from the air by wet or dry deposition(SRC). Itraconazole does not contain chromophores that absorb at wavelengths >290 nm(3), and therefore is not expected to be susceptible to direct photolysis by sunlight(SRC).

While itraconazole is a relatively safe medication, there are some adverse side effects associated with its use. Cardiotoxicity is a rare adverse effect. Itraconazole can decrease heart contractility and left ventricular ejection fraction. The risk of cardiotoxicity increases with a dose greater than 400 mg/day. While most patients' heart function improves after discontinuing itraconazole, some require a transplant. Another adverse effect is hepatotoxicity, which often presents as a reversible increase in aminotransferase levels. This side effect can be minimized with intermittent or short-term dosing. In patients already being treated for hypertension, itraconazole can cause resistant hypertension. The most common adverse effects are gastrointestinal disturbances, such as nausea, mild diarrhea, vomiting, and abdominal pain. Researchers have reported these side effects in 2% to 39% of patients who have used itraconazole. When itraconazole administration is via the intravenous formulation, there is also a risk of injection site reactions, headache, and rash.

Toxic trough levels for itraconazole are over 3 mcg/mL. There is no specific antidote available.

Itraconazole interacts with 14-α demethylase, a cytochrome P-450 enzyme necessary to convert lanosterol to ergosterol. As ergosterol is an essential component of the fungal cell membrane, inhibition of its synthesis results in increased cellular permeability causing leakage of cellular contents. Itraconazole may also inhibit endogenous respiration, interact with membrane phospholipids, inhibit the transformation of yeasts to mycelial forms, inhibit purine uptake, and impair triglyceride and/or phospholipid biosynthesis.

The Koc of itraconazole is estimated as 6,600(SRC), using a log Kow of 5.66(1) and a regression-derived equation(2). According to a classification scheme(3), this estimated Koc value suggests that itraconazole is expected to be immobile in soil. The pKa of itraconazole is 3.7(4), indicating that this compound will exist almost entirely in the cation form in the environment and cations generally adsorb more strongly to soils containing organic carbon and clay than their neutral counterparts(5).

/CASE REPORTS/ Itraconazole is a widely prescribed triazole antifungal drug, often given for long periods. The authors report five cases of tremor related to itraconazole therapy, which occurred within 1-12 months of initiating treatment and resolved gradually following itraconazole withdrawal.

/CASE REPORTS/ ... Three patients with apparent itraconazole-induced liver injury were studied. Clinical, laboratory, serologic, and histologic data of all three cases were analyzed. All three patients developed a biochemical-histologic pattern of cholestatic liver injury with damage to the interlobular bile ducts. Beginning ductopenia was present in two, suggesting that itraconazole might be responsible for the occurrence of prolonged drug-induced cholangiopathy. Jaundice was the presenting symptom in all three. It was not accompanied by clinical hallmarks of hypersensitivity, which is suggestive for metabolic rather than for immunoallergic idiosyncrasy. Itraconazole-induced liver injury presents with a cholestatic pattern of injury with damage to the interlobular bile ducts, possibly leading to ductopenia. ...

/CASE REPORTS/ Itraconazole is widely used to treat onychomycosis because of its significant therapeutic effects. An otherwise healthy 30-year-old man treated with itraconazole developed frequent premature ventricular contractions (PVC). He presented with a dry cough and palpitation. The results of 12-lead electrocardiography (ECG) were essentially normal, but Holter ECG revealed 17,484 (18%) uniform PVC, including 4 short runs among 96,930 beats/day. Another Holter ECG after withdrawing itraconazole revealed 1,032 premature atrial contractions but no PVC. The corrected QT interval was 0.39 s without itraconazole, 0.41 s with itraconazole, and 0.43 s when multiple PVC were documented. Itraconazole inhibits the fungal cytochrome P450 that is involved in fungal cell membrane formation, interrupts human cytochrome P450A4 in the liver and causes adverse interactions with various drugs such as antiarrythmics, but its cardiac side-effects are obscure. Both patients and physicians should be aware that itraconazole can cause PVC as a side-effect.

/CASE REPORTS/ An 80-year-old man was admitted to the hospital with a diagnosis of pulmonary aspergilloma. A new azole antifungal agent, D 0870, was administered to the patient for 7 days orally, and itraconazole (400 mg/day) was started. After 1 month of chemotherapy, facial and pretibial edema were observed and the patient's serum potassium concentration decreased to 2.5 mEq/L. A chest radiograph disclosed cardiomegaly with cardiac effusion and right pleural effusion on admission. The serum potassium concentration rose after the cessation of itraconazole therapy. The serum ITCZ concentration remained high for 2 weeks after admission. Although reports of hypopotassemia induced by ITCZ are rare, /investigators/ concluded that blood concentrations should be monitored more carefully when treating pulmonary aspergilloma patients with high-dose regimens of ITCZ.

For more Human Toxicity Excerpts (Complete) data for Itraconazole (21 total), please visit the HSDB record page.

The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies currently marketed prescription drug products, including itraconazole, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.

J02AC02

J - Antiinfectives for systemic use

QJ - Antiinfectives for systemic use

J02AC02

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 also has a marked affinity for lipids. Only 0.2% of the itraconazole in plasma is present as the free drug.

Itraconazole is an antifungal agent that inhibits cell growth and promotes cell death of fungi. It exhibits in vitro activity against _Blastomyces dermatitidis_, _Histoplasma capsulatum_, _Histoplasma duboisii_, _Aspergillus flavus_, _Aspergillus fumigatus_, and _Trichophyton_ species.

Itraconazole mediates its antifungal activity by inhibiting 14α-demethylase, a fungal cytochrome P450 enzyme that converts lanosterol to ergosterol, a vital component of fungal cell membranes. The azole nitrogen atoms in the chemical structure of itraconazole form a complex with the active site, or the haem iron, of the fungal enzyme to impede its function. The accumulation of lanosterol and 14-methylated sterols results in increased permeability of the fungal cell membrane, and modified membrane-bound enzyme activity, and dysregulated chitin synthesis. Other proposed mechanisms of action of itraconazole include the inhibition of fungal cytochrome c oxidative and peroxidative enzymes that also lead to the disruption of fungal cell membranes.

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

The terminal half-life of itraconazole generally ranges from 16 to 28 hours after a single dose and increases to 34 to 42 hours with repeated dosing. The metabolite of itraconazole is excreted from the plasma more rapidly than the parent compound.

Itraconazole is extensively metabolized in the liver. In vitro studies have shown that CYP3A4 is the major enzyme involved in the metabolism of itraconazole. While itraconazole can be metabolized to more than 30 metabolites, the main metabolite is hydroxyitraconazole. Hydroxyitraconazole has in vitro antifungal activity comparable to itraconazole; trough plasma concentrations of this metabolite are about twice those of the parent compound. Other metabolites include keto-itraconazole and N-dealkyl-itraconazole.

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.

Itraconazole (ITZ) is metabolized in vitro to three inhibitory metabolites: hydroxy-itraconazole (OH-ITZ), keto-itraconazole (keto-ITZ), and N-desalkyl-itraconazole (ND-ITZ). The goal of this study was to determine the contribution of these metabolites to drug-drug interactions caused by ITZ. Six healthy volunteers received 100 mg ITZ orally for 7 days, and pharmacokinetic analysis was conducted at days 1 and 7 of the study. The extent of CYP3A4 inhibition by ITZ and its metabolites was predicted using this data. ITZ, OH-ITZ, keto-ITZ, and ND-ITZ were detected in plasma samples of all volunteers. A 3.9-fold decrease in the hepatic intrinsic clearance of a CYP3A4 substrate was predicted using the average unbound steady-state concentrations (C(ss,ave,u)) and liver microsomal inhibition constants for ITZ, OH-ITZ, keto-ITZ, and ND-ITZ. Accounting for circulating metabolites of ITZ significantly improved the in vitro to in vivo extrapolation of CYP3A4 inhibition compared to a consideration of ITZ exposure alone.

Itraconazole is extensively metabolized by the liver into a large number of metabolites, including hydroxyitraconazole, the major metabolite. The main metabolic pathways are oxidative scission of the dioxolane ring, aliphatic oxidation at the 1-methylpropyl substituent, N-dealkylation of this 1-methylpropyl substituent, oxidative degradation of the piperazine ring and triazolone scission. Route of Elimination: Itraconazole is metabolized predominately by the cytochrome P450 3A4 isoenzyme system (CYP3A4) in the liver, resulting in the formation of several metabolites, including hydroxyitraconazole, the major metabolite. Fecal excretion of the parent drug varies between 3-18% 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. Half Life: 21 hours

304NUG5GF4

ITRACONAZOLE

Established Pharmacologic Class [EPC] - Azole Antifungal

Chemical Structure [CS] - Azoles

Mechanisms of Action [MoA] - Cytochrome P450 3A4 Inhibitors

Mechanisms of Action [MoA] - P-Glycoprotein Inhibitors

Substances that destroy fungi by suppressing their ability to grow or reproduce. They differ from FUNGICIDES, INDUSTRIAL because they defend against fungi present in human or animal tissues.

Compounds that specifically inhibit STEROL 14-DEMETHYLASE. A variety of azole-derived ANTIFUNGAL AGENTS act through this mechanism.

Drugs and compounds which inhibit or antagonize the biosynthesis or actions of CYTOCHROME P-450 CYP3A.

Itraconazole is rapidly absorbed after oral administration. As oral capsules, peak plasma concentrations of itraconazole are reached within two to five hours. The observed absolute oral bioavailability of itraconazole is about 55%. Itraconazole exposure is lower with the capsule formulation than with the oral solution when the same dose of the drug is given. Maximal drug absorption is achieved under adequate gastric acidity. 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 2.0 μg/mL after oral administration of 100 mg once daily, 200 mg once daily and 200 mg b.i.d., respectively.

Itraconazole is excreted mainly as inactive metabolites in urine (35%) and in feces (54%) within one week of an oral solution dose. Renal excretion of itraconazole and the active metabolite hydroxyitraconazole 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 the re-distribution of itraconazole from keratinous tissues appears to be negligible, the elimination of itraconazole from these tissues is related to epidermal regeneration. Contrary to plasma, the concentration in skin persists for two to four weeks after discontinuation of a 4-week treatment and in nail keratin – where itraconazole can be detected as early as one week after the start of treatment – for at least six months after the end of a 3-month treatment period.

The volume of distribution is more than 700 L in adults. Itraconazole is lipophilic and extensively distributed into tissues. Concentrations in the 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.

The mean total plasma clearance following intravenous administration is 278 mL/min. Itraconazole clearance decreases at higher doses due to saturable hepatic metabolism.

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 /provided/.

MEDICATION

Use (kg; approx.) in Germany (2009): >500

For the treatment of the following fungal infections in immunocompromised and non-immunocompromised patients: pulmonary and extrapulmonary blastomycosis, histoplasmosis, aspergillosis, and onychomycosis.

Impurities: 4-[4-[4-(4-methoxyphenyl)piperazin-1-yl]phenyl]-2-[(1RS)-1-methylpropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one; 4-[4-[4-[4-[[cis-2-(2,4-dichlorophenyl)-2-(4H-1,2,4-triazol-4-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-one; 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-propyl-2,4-dihydro-3H-1,2,4-triazol-3-one; 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-(1-methylethyl)-2,4-dihydro-3H-1,2,4-triazol-3-one; 4-[4-[4-[4-[[trans-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-one; 2-butyl-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]-2,4-dihydro-3H-1,2,4-triazol-3-one; 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-[[cis-2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methyl]-2,4-dihydro-3H-1,2,4-triazol-3-one.

Animal Drugs -> FDA Approved Animal Drug Products (Green Book) -> Active Ingredients

Fungicides