ITRACONYX

First synthesized in the early 1980s, itraconazole is a broad-spectrum triazole antifungal agent used to treat a variety of infections.

It is a 1:1:1:1 racemic mixture of four diastereomers, made up of two enantiomeric pairs, each possessing three chiral centers.

Itraconazole was first approved in the

US in 1992 6 and is available Oral.

While the intravenous formulation of the drug was formerly available, it was discontinued in the US in 2007.

Itraconazole is indicated for the treatment of the following fungal infections in immunocompromised and non-immunocompromised patients: 5, 6 Blastomycosis, pulmonary and extrapulmonary Histoplasmosis, including chronic cavitary pulmonary disease and disseminated, nonmeningeal histoplasmosis, and Aspergillosis, pulmonary and extrapulmonary, in patients who are intolerant of or who are refractory to amphotericin B therapy It is also indicated for the treatment of the following fungal infections in non-immunocompromised patients: 5 Onychomycosis of the toenail, with or without fingernail involvement, due to dermatophytes (tinea unguium) Onychomycosis of the fingernail due to dermatophytes (tinea unguium).

Itraconazole oral solution is indicated for the treatment of oropharyngeal and esophageal candidiasis.

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 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. 1, 5 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.

The volume of distribution is more than 700 L in adults. 4, 5 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.

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, 2 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

Hover over products below to view reaction partners Itraconazole Hydroxyitraconazole.

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 terminal half-life of itraconazole generally ranges from 16-28 hours after a single dose and increases to 34-42 hours with repeated dosing.

The metabolite of itraconazole is excreted from the plasma more rapidly than the parent compound.

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

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In rats, the oral and intraperitoneal LD 50 values were >320 mg/kg and 100 mg/kg, respectively.

There is limited clinical information regarding itraconazole overdoses.

Reported toxic trough levels are over 3 mcg/mL.

Itraconazole is not removed by dialysis; thus, supportive measures should be initiated in the event of an overdose.

There is no known antidote to itraconazole poisoning.

Itraconazole 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 use or reinstitution of treatment with itraconazole is strongly discouraged unless there is a serious or life-threatening situation where the expected benefit exceeds the risk.

Life-threatening cardiac dysrhythmias and/or sudden death have occurred in patients using drugs such as cisapride, pimozide, methadone, or quinidine concomitantly with itraconazole and/or other CYP3A4 inhibitors.

Concomitant administration of these drugs with itraconazole is contraindicated.

Itraconazole capsules should not be administered for the treatment of onychomycosis in patients with evidence of ventricular dysfunction such as congestive heart failure (CHF) or a history of CHF.

Itraconazole capsules should not be used for other indications in patients with evidence of ventricular dysfunction unless the benefit clearly outweighs the risk.

For patients with risk factors for congestive heart failure, physicians should carefully review the risks and benefits of itraconazole therapy.

These risk factors include cardiac disease such as ischemic and valvular disease; significant pulmonary disease such as chronic obstructive pulmonary disease; and renal failure and other edematous disorders.

Such patients should be informed of the signs and symptoms of CHF, should be treated with caution, and should be monitored for signs and symptoms of CHF during treatment.

If signs or symptoms of

CHF appear during administration of itraconazole capsules, discontinue administration.

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 has been associated with reports of congestive heart failure.

In postmarketing 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 co-administering itraconazole and calcium channel blockers due to an increased risk of CHF.

Concomitant administration of itraconazole and felodipine or nisoldipine is contraindicated.

Cases of

CHF, peripheral edema, and pulmonary edema have been reported in the postmarketing period among patients being treated for onychomycosis and/or systemic fungal infections.

Pseudoaldosteronism, manifested by the onset of hypertension or worsening of hypertension, and abnormal laboratory findings (hypokalemia, low serum renin and aldosterone, and elevated 11deoxycortisol), has been reported with itraconazole use in the postmarketing setting.

Monitor blood pressure and potassium levels and manage as necessary.

Management of pseudoaldosteronism may include discontinuation of itraconazole, substitution with an appropriate antifungal drug that is not associated with pseudoaldosteronism, or use of aldosterone receptor antagonists.

Itraconazole has 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.

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.

Solution has been demonstrated effective for oral and/or esophageal candidiasis.

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.

Coadministration of a number of CYP3A4 substrates are contraindicated with itraconazole.

Some examples of drugs for which plasma concentrations increase are: 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, finerenone, voclosporin.

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.

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.

Some specific examples are listed in PRECAUTIONS: Drug Interactions.

Coadministration with venetoclax is contraindicated in patients with CLL/SLL during the dose initiation and ramp-up phase of venetoclax due to the potential for an increased risk of tumor lysis syndrome.

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

Itraconazole 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 to patients with hypersensitivity to other azoles.

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

Itraconazole capsules must be swallowed whole.

Itraconazole capsule is a different preparation than itraconazole Oral Solution and should not be used interchangeably.

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.

A daily dose of to 400 mg is recommended.

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 three months and until clinical parameters and laboratory tests indicate that the active fungal infection has subsided.

An inadequate period of treatment may lead to recurrence of active infection.

Itraconazole capsules and itraconazole Oral

Solution should not be used interchangeably.

Only the oral solution has been demonstrated effective for oral and/or esophageal candidiasis.

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

Fingernails only: The recommended dosing regimen is 2 treatment pulses, each consisting of 200 mg (2 capsules) b.i.d. (400 mg/day) for 1 week.

The pulses are separated by a 3-week period without itraconazole.

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.

Limited data are available on the use of oral itraconazole in patients with hepatic impairment.

Itraconazole capsules, USP are supplied as follows: 100 mg: Blue opaque cap/pink transparent body size “0” hard gelatin capsules having imprinting “A” on cap with black ink and “175” on body with black ink filled with white to off-white pellets.

NDC 62332-204-30 Bottle of 30 Capsules with child-resistant closure NDC 62332-204-90 Bottle of 90 Capsules with child-resistant closure NDC 62332-204-71 Bottle of 500 Capsules NDC 62332-204-10 Unit Dose Capsules of 100 (Blisters of 10) NDC 62332-204-04 7 Blister Packs x 4 Capsules Each (7 Day Treatment Pack) Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) .

Protect from light and moisture.

Keep out of reach of children.

Information available at or call 1-866-210-9797.

Itraconazole was found to cause a dose-related increase in maternal toxicity, embryotoxicity, and teratogenicity in rats at dosage levels of approximately to 160 mg/kg/day (1 to 4 times the MRHD based on body surface area comparisons), and in mice at dosage levels of approximately 80 mg/kg/day (1 time the MRHD based on body surface area comparisons).

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 should be used for the treatment of systemic fungal infections in pregnancy only if the benefit outweighs the potential risk.

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

Itraconazole should not be administered to women of childbearing potential for the treatment of onychomycosis unless they are using effective measures to prevent pregnancy and they begin therapy on the second or third day following the onset of menses.

Highly effective contraception should be continued throughout itraconazole therapy and for 2 months following the end of treatment.

During postmarketing experience, cases of congenital abnormalities have been reported. See ADVERSE REACTIONS: Postmarketing Experience..

Itraconazole is excreted in human milk; therefore, the expected benefits of itraconazole therapy for the mother should be weighed against the potential risk from exposure of itraconazole to the infant.

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.

The efficacy and safety of itraconazole 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 (0.5 times the MRHD of 400 mg based on body surface area comparisons).

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 (2 times the MRHD based on body surface area comparisons) over 1 year or 160 mg/kg/day (4 times the MRHD based on body surface area comparisons) for 6 months, itraconazole induced small tooth pulp with hypocellular appearance in some rats.

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.