ITRACONAZOLE- itraconazole capsule
Accord Healthcare Inc.
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.
Itraconazole is 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:
(±)-1-[( R*)- sec-butyl]-4-[ p-[4-[ p-[[(2 R*,4 S*)-2-(2,4-dichlorophenyl)-2-(1 H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1-piperazinyl]phenyl]-Δ 2 -1,2,4-triazolin-5-one mixture with (±)-1-[( R*)- sec-butyl]-4-[ p-[4-[ p-[[(2 S*,4 R*)-2-(2,4-dichlorophenyl)-2-(1 H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1-piperazinyl]phenyl]-Δ 2 -1,2,4-triazolin-5-one
(±)-1-[( RS)- sec-butyl]-4-[ p-[4-[ p-[[(2 R,4 S)-2-(2,4-dichlorophenyl)-2-(1 H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1-piperazinyl]phenyl]-Δ 2 -1,2,4-triazolin-5-one
Itraconazole has a molecular formula of C 35 H 38 Cl 2 N 8 O 4 and a molecular weight of 705.64. It is a white to slightly yellowish powder. It is insoluble in water, very slightly soluble in alcohols, and freely soluble in dichloromethane. It has a pKa of 3.70 (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 coated on sugar spheres. Inactive ingredients are hard gelatin capsule, hypromellose, polyglykol (PEG 20,000), purified talc, and sugar spheres (maize starch and sucrose). Components of the gelatin capsule include FD&C Blue No. 1, FD&C Blue No. 2, gelatin, D&C Red No. 28, and titanium dioxide. The printing ink contains potassium hydroxide, propylene glycol, shellac, and titanium dioxide.
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 C max 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. 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.
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., H 2 -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 H 2 -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)
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