Itraconazole Oral

ITRACONAZOLE ORAL- itraconazole solution
Dash Pharmaceuticals LLC

BOXED WARNING

Congestive Heart Failure, Cardiac Effects and Drug Interactions: If signs or symptoms of congestive heart failure occur during administration of itraconazole oral solution, continued itraconazole use should be reassessed. 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 oral solution: 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, 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:

Structural Formula

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

or

4-[4-[4-[4-[[Cis-2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy] phenyl]piperazin1-yl] phenyl]-2-[(1RS)-1-methyl propyl]-2,4-dihydro-3H-1,2,4-triazol-3-one

Itraconazole has a molecular formula of C35 H38 Cl2 N8 O4 and a molecular weight of 705.63. It is a white or almost white powder. It is freely soluble in methylene chloride, sparingly soluble in tetrahydrofuran, very slightly soluble in alcohol, practically insoluble in water. It has a pKa of 3.70 (based on extrapolation of values obtained from methanolic solutions) and a log (n-octanol/aq. Buffer of pH: 8.1) partition coefficient of 5.66 at pH 8.1.

Itraconazole oral solution contains 10 mg of itraconazole USP per mL, solubilized by hydroxypropyl-β-cyclodextrin (400 mg/mL) as a molecular inclusion complex.

Itraconazole oral solution is clear, colorless to yellowish brown liquid with a target pH of 2. Other ingredients are ascorbic acid, hydrochloric acid, propylene glycol, purified water, non crystallizing sorbitol solution, saccharin sodium, sodium hydroxide, ART Cherry flavor.

CLINICAL PHARMACOLOGY

Pharmacokinetics and Metabolism:

Itraconazole

General Pharmacokinetic Characteristics

Peak plasma concentrations are reached within 2.5 hours following administration of the oral solution. As a consequence of non-linear pharmacokinetics, itraconazole accumulates in plasma during multiple dosing. Steadystate concentrations are generally reached within about 15 days, with Cmax and AUC values 4 to 7-fold higher than those seen after a single dose. Steady-state Cmax values of about 2 mcg/mL are reached after oral administration of 200 mg once daily. 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 administration of the oral solution. Peak plasma concentrations of itraconazole are reached within 2.5 hours following administration of the oral solution under fasting conditions. The observed absolute bioavailability of itraconazole under fed conditions is about 55% and increases by 30% when the oral solution is taken in fasting conditions. Itraconazole exposure is greater with the oral solution than with the capsule formulation 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 one 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.

Special Populations:

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.×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 to 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 to 79 mL/min), moderate (defined in this study as CrCl 20 to 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 to 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.)

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 twofold 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 chornic patients during long-term use of itraconazole. (See CONTRAINDICATIONS, PRECAUTIONS: Drug Interactions and DOSAGE AND ADMINISTRATION.)

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