SPORANOX® (itraconazole) Capsules BOXED WARNING

SPORANOX

(itraconazole)

Capsules

BOXED WARNING

Congestive Heart Failure, Cardiac Effects and Drug Interactions

Congestive Heart Failure and Cardiac Effects:

• SPORANOX

(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 SPORANOX

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 a number of CYP3A4 substrates are contraindicated with

SPORANOX

. Some examples of drugs that are contraindicated for

coadministration with SPORANOX

Capsules 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.

• Coadministration with colchicine, fesoterodine and solifenacin is contraindicated in

subjects with varying degrees of renal or hepatic impairment.

• Coadministration with eliglustat is contraindicated in subjects that are poor or

intermediate metabolizers of CYP2D6 and in subjects taking strong or moderate

CYP2D6 inhibitors.

• Coadministration with venetoclax is contraindicated in patients with chronic

lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) during the dose

initiation and ramp-up phase of venetoclax. 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

SPORANOX

is the brand name for 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:

(±)-1-[(R*)-sec-butyl]-4-[p-[4-[p-[[(2R*,4S*)-2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-

ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1-piperazinyl]phenyl]-Δ

-1,2,4-triazolin-5-one

mixture with (±)-1-[(R*)-sec-butyl]-4-[p-[4-[p-[[(2S*,4R*)-2-(2,4-dichlorophenyl)-2-(1H-

1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1-piperazinyl]phenyl]-Δ

-1,2,4-

triazolin-5-one

(±)-1-[(RS)-sec-butyl]-4-[p-[4-[p-[[(2R,4S)-2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-

ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1-piperazinyl]phenyl]-Δ

-1,2,4-triazolin-5-one

Itraconazole has a molecular formula of C

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.

SPORANOX

Capsules contain 100 mg of itraconazole coated on sugar spheres (composed of

sucrose, maize starch, and purified water). Inactive ingredients are hard gelatin capsule,

hypromellose, polyethylene glycol (PEG) 20,000, titanium dioxide, FD&C Blue No. 1, FD&C

Blue No. 2, D&C Red No. 22 and D&C Red No. 28.

Meets USP Dissolution Test 2.

CLINICAL PHARMACOLOGY

Pharmacokinetics and Metabolism:

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 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.

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 SPORANOX

(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

-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 SPORANOX

Capsules are

administered with an acidic beverage (such as a non-diet cola). When SPORANOX

Capsules

were administered as a single 200-mg dose under fasted conditions with non-diet cola after

ranitidine pretreatment, a H

-receptor antagonist, itraconazole absorption was comparable to that

observed when SPORANOX

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

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.

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 six months after the end of a 3-month treatment period.

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 m

, 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 (T

max

, C

max

, and

AUC

0-8h

). 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.)

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 C

max

(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 cirrhotic patients

during long-term use of itraconazole. (See CONTRAINDICATIONS, PRECAUTIONS: Drug

Interactions 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 SPORANOX

Capsules, SPORANOX

should be discontinued. (See BOXED WARNING, CONTRAINDICATIONS, WARNINGS,

PRECAUTIONS: Drug Interactions and ADVERSE REACTIONS: Post-marketing Experience

for more information.)

MICROBIOLOGY

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.

Antimicrobial Activity:

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).

Susceptibility Testing Methods:

For specific information regarding susceptibility test interpretive criteria and associated test

methods and quality control standards recognized by FDA for this drug, please see:

https://www.fda.gov/STIC.

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

C-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

SPORANOX

(itraconazole) Capsules are indicated for the treatment of the following fungal

infections in immunocompromised and non-immunocompromised patients:

1. Blastomycosis, pulmonary and extrapulmonary

2. Histoplasmosis, including chronic cavitary pulmonary disease and disseminated, non-

meningeal histoplasmosis, and

3. 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.

SPORANOX

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), and

2. 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.)

Description of Clinical Studies:

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 SPORANOX

Capsules) in which patients with onychomycosis of the

toenails received 200 mg of SPORANOX

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 SPORANOX

Capsules) in which patients with onychomycosis of the fingernails received

a 1-week course (pulse) of 200 mg of SPORANOX

Capsules b.i.d., followed by a 3-week period

without SPORANOX

, which was followed by a second 1-week pulse of 200 mg of

SPORANOX

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.

CONTRAINDICATIONS

Congestive Heart Failure:

SPORANOX

(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 SPORANOX

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. (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. 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.

SPORANOX

should not be administered for the treatment of onychomycosis to pregnant patients

or to women contemplating pregnancy.

SPORANOX

is 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 SPORANOX

to patients with

hypersensitivity to other azoles.

WARNINGS

Hepatic Effects:

SPORANOX

has 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

SPORANOX

use or reinstitution of treatment with SPORANOX

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 SPORANOX

and/or

other CYP3A4 inhibitors. Concomitant administration of these drugs with SPORANOX

contraindicated. (See BOXED WARNING, CONTRAINDICATIONS, and PRECAUTIONS:

Drug Interactions.)

Cardiac Disease:

SPORANOX

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. SPORANOX

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 SPORANOX

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 SPORANOX

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.

SPORANOX

has 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 co-administering itraconazole and calcium channel

blockers due to an increased risk of CHF. Concomitant administration of SPORANOX

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:

SPORANOX

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.

Interchangeability:

SPORANOX

(itraconazole) Capsules and SPORANOX

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.

PRECAUTIONS

General:

SPORANOX

(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 SPORANOX

treatment, including

some cases within the first week. It is recommended that liver function monitoring be considered

in all patients receiving SPORANOX

. 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 SPORANOX

Capsules, the treatment should be

discontinued.

Immunocompromised Patients:

In some immunocompromised patients (e.g., neutropenic, AIDS or organ transplant patients), the

oral bioavailability of SPORANOX

capsules may be decreased. Therefore, the dose should be

adjusted based on the clinical response in these patients.

Cystic Fibrosis:

If a cystic fibrosis patient does not respond to SPORANOX

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 SPORANOX

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 SPORANOX

Capsules and Oral Solution. Only the Oral Solution has been demonstrated effective for

oral and/or esophageal candidiasis. SPORANOX

Capsules should not be used

interchangeably with SPORANOX

Oral Solution.

• Instruct patients to take SPORANOX

Capsules with a full meal. SPORANOX

Capsules

must be swallowed whole.

• Instruct patients about the signs and symptoms of congestive heart failure, and if these

signs or symptoms occur during SPORANOX

administration, they should discontinue

SPORANOX

and contact their healthcare provider immediately.

• Instruct patients to stop SPORANOX

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.

Drug Interactions:

Effect of SPORANOX

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, SPORANOX

has 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,

Torsade 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 it 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 SPORANOX

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 SPORANOX

Table 1: Drug Interactions with SPORANOX

that Affect Concomitant Drug

Concentrations

Examples of Concomitant Drugs Within

Class

Prevention or Management

Drug Interactions with SPORANOX

that Increase Concomitant Drug Concentrations and

May Increase Risk of Adverse Reactions Associated with the Concomitant Drug

Alpha Blockers

Alfuzosin

Silodosin

Tamsulosin

Not recommended during and 2 weeks after

SPORANOX

treatment.

Analgesics

Methadone

Contraindicated during and 2 weeks after

SPORANOX

treatment.

Fentanyl

Not recommended during and 2 weeks after

SPORANOX

treatment.

Alfentanil

Buprenorphine (IV and sublingual)

Oxycodone

Sufentanil

Monitor for adverse reactions. Concomitant drug

dose reduction may be necessary.

Antiarrhythmics

Disopyramide

Dofetilide

Dronedarone

Quinidine

Contraindicated during and 2 weeks after

SPORANOX

treatment.

Digoxin

Monitor for adverse reactions. Concomitant drug

dose reduction may be necessary.

Antibacterials

Bedaquiline

Concomitant SPORANOX

not recommended for

more than 2 weeks at any time during bedaquiline

treatment.

Rifabutin

Not recommended 2 weeks before, during, and

2 weeks after SPORANOX

treatment. See also

Table 2.

Clarithromycin

Monitor for adverse reactions. Concomitant drug

dose reduction may be necessary. See also

Table 2.

Trimetrexate

Monitor for adverse reactions.

Concomitant drug

dose reduction may be necessary.

Anticoagulants and Antiplatelets

Ticagrelor

Contraindicated during and 2 weeks after

SPORANOX

treatment.

Apixaban

Rivaroxaban

Vorapaxar

Not recommended during and 2 weeks after

SPORANOX

treatment.

Cilostazol

Dabigatran

Warfarin

Monitor for adverse reactions. Concomitant drug

dose reduction may be necessary.

Anticonvulsants

Carbamazepine

Not recommended 2 weeks before, during, and

2 weeks after SPORANOX

treatment. See also

Table 2.

Antidiabetic Drugs

Repaglinide

Saxagliptin

Monitor for adverse reactions. Concomitant drug

dose reduction may be necessary.

Antihelminthics, Antifungals and Antiprotozoals

Isavuconazonium

Contraindicated during and 2 weeks after

SPORANOX

treatment.

Praziquantel

Monitor for adverse reactions. Concomitant drug

dose reduction may be necessary.

Artemether-lumefantrine

Quinine

Monitor for adverse reactions.

Antimigraine Drugs

Ergot alkaloids (e.g., dihydroergotamine,

ergotamine)

Contraindicated during and 2 weeks after

SPORANOX

treatment.

Eletriptan

Monitor for adverse reactions. Concomitant drug

dose reduction may be necessary.

Antineoplastics

Irinotecan

Contraindicated during and 2 weeks after

SPORANOX

treatment.

Venetoclax

Contraindicated during the dose initiation and

ramp-up phase in patients with CLL/SLL. Refer to

the venetoclax prescribing information for dosing

and safety monitoring instructions.

Mobocertinib

Avoid use during and 2 weeks after SPORANOX

treatment.

Axitinib

Bosutinib

Cabazitaxel

Cabozantinib

Ceritinib

Cobimetinib

Crizotinib

Dabrafenib

Dasatinib

Docetaxel

Ibrutinib

Lapatinib

Nilotinib

Olaparib

Pazopanib

Sunitinib

Trabectedin

Trastuzumab-

emtansine

Vinca alkaloids

Avoid use during and 2 weeks after SPORANOX

treatment.

Entrectinib

Pemigatinib

Talazoparib

Refer to the entrectinib, pemigatinib and

talazoparib prescribing information for dosing

instructions if concomitant use cannot be avoided.

Glasdegib

Refer to the glasdegib prescribing information for

safety monitoring if concomitant use cannot be

avoided.

Bortezomib

Brentuximab-

vedotin

Busulfan

Erlotinib

Gefitinib

Idelalisib

Imatinib

Ixabepilone

Nintedanib

Panobinostat

Ponatinib

Ruxolitinib

Sonidegib

Tretinoin (oral)

Vandetanib

Monitor for adverse reactions.

Concomitant drug

dose reduction may be necessary. For idelalisib,

see also Table 2.

Cardiovascular Drugs, Miscellaneous

Ivabradine

Ranolazine

Contraindicated during and 2 weeks after

SPORANOX

treatment.

Aliskiren

Riociguat

Sildenafil (for pulmonary hypertension)

Tadalafil (for pulmonary hypertension)

Not recommended during and 2 weeks after

SPORANOX

treatment. For sildenafil and

tadalafil, see also Urologic Drugs below.

Bosentan

Guanfacine

Monitor for adverse reactions. Concomitant drug

dose reduction may be necessary.

Contraceptives*

Dienogest

Ulipristal

Monitor for adverse reactions.

Diuretics

Eplerenone

Finerenone

Contraindicated during and 2 weeks after

SPORANOX

treatment.

Gastrointestinal Drugs

Cisapride

Naloxegol

Contraindicated during and 2 weeks after

SPORANOX

treatment.

Aprepitant

Loperamide

Monitor for adverse reactions. Concomitant drug

dose reduction may be necessary.

Netupitant

Monitor for adverse reactions.

Immunosuppressants

Voclosporin

Contraindicated during and for 2 weeks after

SPORANOX

treatment.

Everolimus

Sirolimus

Temsirolimus (IV)

Not recommended during and 2 weeks after

SPORANOX

treatment.

Budesonide

(inhalation)

Budesonide (non-

inhalation)

Ciclesonide

(inhalation)

Cyclosporine (IV)

Cyclosporine (non-

IV)

Dexamethasone

Fluticasone

(inhalation)

Fluticasone (nasal)

Methylprednisolone

Tacrolimus (IV)

Tacrolimus (oral)

Monitor for adverse reactions. Concomitant drug

dose reduction may be necessary.

Lipid-Lowering Drugs

Lomitapide

Lovastatin

Simvastatin

Contraindicated during and 2 weeks after

SPORANOX

treatment.

Atorvastatin

Monitor for drug adverse reactions. Concomitant

drug dose reduction may be necessary.

Respiratory Drugs

Salmeterol

Not recommended during and 2 weeks after

SPORANOX

treatment.

SSRIs, Tricyclics and Related Antidepressants

Venlafaxine

Monitor for adverse reactions. Concomitant drug

dose reduction may be necessary.

Urologic Drugs

Avanafil

Contraindicated during and 2 weeks after

SPORANOX

treatment.

Fesoterodine

Patients with moderate to severe renal or hepatic

impairment: Contraindicated during and 2 weeks

after SPORANOX

treatment.

Other patients: Monitor for adverse reactions.

Concomitant drug dose reduction may be

necessary.

Solifenacin

Patients with severe renal or moderate to severe

hepatic impairment: Contraindicated during and

2 weeks after SPORANOX

treatment.

Other patients: Monitor for adverse reactions.

Concomitant drug dose reduction may be

necessary.

Darifenacin

Vardenafil

Not recommended during and 2 weeks after

SPORANOX

treatment.

Dutasteride

Oxybutynin

Sildenafil (for erectile dysfunction)

Tadalafil (for erectile dysfunction and

benign prostatic hyperplasia)

Tolterodine

Monitor for adverse reactions. Concomitant drug

dose reduction may be necessary. For sildenafil

and tadalafil, see also Cardiovascular Drugs

above.

Miscellaneous Drugs and Other Substances

Colchicine

Patients with renal or hepatic impairment:

Contraindicated during and 2 weeks after

SPORANOX

treatment.

Other patients: Not recommended during and

2 weeks after SPORANOX

treatment.

Eliglustat

CYP2D6 EMs

taking a strong or moderate

CYP2D6 inhibitor, CYP2D6 IMs

, or CYP2D6

PMs

: Contraindicated during and 2 weeks after

SPORANOX

treatment.

CYP2D6 EMs

not taking a strong or moderate

CYP2D6 inhibitor: Monitor for adverse reactions.

Eliglustat dose reduction may be necessary.

Lumacaftor/Ivacaftor

Not recommended 2 weeks before, during, and

2 weeks after SPORANOX

treatment.

Alitretinoin (oral)

Cabergoline

Cannabinoids

Cinacalcet

Galantamine

Ivacaftor

Monitor for adverse reactions. Concomitant drug

dose reduction may be necessary.

Valbenazine

Concomitant drug dose reduction is necessary.

Refer to the valbenazine prescribing information

for dosing instructions.

Vasopressin Receptor Antagonists

Conivaptan

Tolvaptan

Not recommended during and 2 weeks after

SPORANOX

treatment.

Drug Interactions with SPORANOX

that Decrease Concomitant Drug Concentrations and

May Reduce Efficacy of the Concomitant Drug

Antineoplastics

Regorafenib

Not recommended during and 2 weeks after

SPORANOX

treatment.

Gastrointestinal Drugs

Saccharomyces boulardii

Not recommended during and 2 weeks after

SPORANOX

treatment.

Nonsteroidal Anti-Inflammatory Drugs

Meloxicam

Concomitant drug dose increase may be necessary.

CYP3A4 inhibitors (including itraconazole) may increase systemic contraceptive hormone concentrations.

Based on clinical drug interaction information with itraconazole.

Based on 400 mg bedaquiline once daily for 2 weeks.

EMs: extensive metabolizers; IMs: intermediate metabolizers, PMs: poor metabolizers

Effect of Other Drugs on SPORANOX

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 SPORANOX

resulting

in either increased or sometimes decreased concentrations of SPORANOX

. Increased

concentrations may increase the risk of adverse reactions associated with SPORANOX

Decreased concentrations may reduce SPORANOX

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 SPORANOX

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 SPORANOX

Table 2: Drug Interactions with Other Drugs that Affect SPORANOX

Concentrations

Examples of Concomitant Drugs Within

Class

Prevention or Management

Drug Interactions with Other Drugs that Increase SPORANOX

Concentrations and May

Increase Risk of Adverse Reactions Associated with SPORANOX

Antibacterials

Ciprofloxacin

Erythromycin

Clarithromycin

Monitor for adverse reactions. SPORANOX

dose

reduction may be necessary.

Antineoplastics

Idelalisib

Monitor for adverse reactions. SPORANOX

dose

reduction may be necessary. See also Table 1.

Antivirals

Cobicistat

Darunavir (ritonavir-boosted)

Elvitegravir (ritonavir-boosted)

Fosamprenavir (ritonavir-boosted)

Indinavir

Ombitasvir/ Paritaprevir/ Ritonavir with or

without Dasabuvir

Ritonavir

Saquinavir

Monitor for adverse reactions. SPORANOX

dose

reduction may be necessary. For, cobicistat,

elvitegravir, indinavir, ombitasvir/ paritaprevir/

ritonavir with or without dasabuvir, ritonavir, and

saquinavir, see also Table 1.

Calcium Channel Blockers

Diltiazem

Monitor for adverse reactions.

SPORANOX

dose

reduction may be necessary. See also Table 1.

Drug Interactions with Other Drugs that Decrease SPORANOX

Concentrations and May

Reduce Efficacy of SPORANOX

Antibacterials

Isoniazid

Rifampicin

Not recommended 2 weeks before and during

SPORANOX

treatment.

Rifabutin

Not recommended 2 weeks before, during, and

2 weeks after SPORANOX

treatment. See also

Table 1.

Anticonvulsants

Phenobarbital

Phenytoin

Not recommended 2 weeks before and during

SPORANOX

treatment.

Carbamazepine

Not recommended 2 weeks before, during, and

2 weeks after SPORANOX

treatment. See also

Table 1.

Antivirals

Efavirenz

Nevirapine

Not recommended 2 weeks before and during

SPORANOX

treatment.

Gastrointestinal Drugs

Drugs that reduce gastric acidity e.g. acid

neutralizing medicines such as aluminum

hydroxide, or acid secretion suppressors

such as H

- 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 SPORANOX

capsules.

Miscellaneous Drugs and Other Substances

Lumacaftor/Ivacaftor

Not recommended 2 weeks before, during, and

2 weeks after SPORANOX

treatment.

Based on clinical drug interaction information with itraconazole.

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 1 time the maximum recommended human

dose [MRHD] of 400 mg/day based on body surface area comparisons). Male rats treated with

25 mg/kg/day (0.6 times the MRHD based on body surface area comparisons) 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 (1.2 times the MRHD based on body

surface area comparisons) 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 (1 time the MRHD based on body surface area comparisons), 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 (4 times the MRHD based on

body surface area comparisons).

Pregnancy: Teratogenic Effects:

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 (1-4 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. SPORANOX

should be used for the treatment of

systemic fungal infections in pregnancy only if the benefit outweighs the potential risk.

SPORANOX

should not be administered for the treatment of onychomycosis to pregnant patients

or to women contemplating pregnancy. SPORANOX

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 SPORANOX

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 SPORANOX

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 SPORANOX

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.

Geriatric Use:

Clinical studies of SPORANOX

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 SPORANOX

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.

Renal Impairment:

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:

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

SPORANOX

. 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 SPORANOX

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.)

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.

SPORANOX

has 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

SPORANOX

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

Vomiting

Diarrhea

Abdominal Pain

Anorexia

Body as a Whole

Edema

Fatigue

Fever

Malaise

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)

Skin and Appendages

Rash*

Pruritus

Central/Peripheral Nervous System

Headache

Dizziness

Psychiatric

Libido Decreased

Somnolence

Cardiovascular

Hypertension

Metabolic/Nutritional

Hypokalemia

Urinary System

Albuminuria

Liver and Biliary System

Hepatic Function Abnormal

Reproductive System, Male

Impotence

* Rash tends to occur more frequently in immunocompromised patients receiving immunosuppressive

medications.

Adverse 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 Therapy

Adverse Event

Incidence (%)

Itraconazole (N=112)

Elevated Liver Enzymes (greater than twice the upper limit of normal)

Gastrointestinal Disorders

Rash

Hypertension

Orthostatic Hypotension

Headache

Malaise

Myalgia

Vasculitis

Vertigo

The 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 pulse 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 Therapy

Adverse Event

Incidence (%)

Itraconazole (N=37)

Rash/Pruritus

Hypertriglyceridemia

The 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

SPORANOX

Capsules 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 SPORANOX

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

SPORANOX

(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 Reactions

Blood and Lymphatic System Disorders:

Leukopenia, neutropenia, thrombocytopenia

Immune System Disorders:

Anaphylaxis; anaphylactic, anaphylactoid and allergic

reactions; serum sickness; angioneurotic edema

Nervous System Disorders:

Peripheral neuropathy, paresthesia, hypoesthesia,

tremor

Eye Disorders:

Visual disturbances, including vision blurred and

diplopia

Ear and Labyrinth Disorders:

Transient or permanent hearing loss

Cardiac Disorders:

Congestive heart failure

Respiratory, Thoracic and Mediastinal Disorders:

Pulmonary edema, dyspnea

Gastrointestinal Disorders:

Pancreatitis, dysgeusia

Hepatobiliary Disorders:

Serious hepatotoxicity (including some cases of fatal

acute liver failure), hepatitis

Skin and Subcutaneous Tissue Disorders:

Toxic epidermal necrolysis, Stevens-Johnson

syndrome, acute generalized exanthematous pustulosis,

erythema multiforme, exfoliative dermatitis,

leukocytoclastic vasculitis, alopecia, photosensitivity,

urticaria

Musculoskeletal 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 edema

Investigations:

Blood creatine phosphokinase increased

There is limited information on the use of SPORANOX

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 SPORANOX

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. Contact a certified poison control center for the most up to date information

on the management of SPORANOX

Capsules overdosage (1-800-222-1222 or www.poison.org).

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

SPORANOX

(itraconazole) Capsules should be taken with a full meal to ensure maximal

absorption. SPORANOX

(itraconazole) Capsules must be swallowed whole.

SPORANOX

Capsules is a different preparation than SPORANOX

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 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.

SPORANOX

Capsules and SPORANOX

Oral Solution should not be used interchangeably.

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

Treatment of Onychomycosis:

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 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 SPORANOX

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

SPORANOX

(itraconazole) Capsules are available containing 100 mg of itraconazole, with a

blue opaque cap and pink transparent body, imprinted with “JANSSEN” and “SPORANOX 100.”

The capsules are supplied in unit-dose blister packs of 3 × 10 capsules (NDC 50458-290-01) and

bottles of 30 capsules (NDC 50458-290-04).

Store at controlled room temperature 15°-25°C (59°-77°F). Protect from light and moisture.

Revised: 02/2024

Manufactured for:

Janssen Pharmaceuticals, Inc.

Titusville, NJ 08560, USA

PATIENT INFORMATION

SPORANOX

(SPOR-ah-nox)

(itraconazole)

Capsules

Read this Patient Information that comes with SPORANOX before you start taking it and each time you get a refill.

There may be new information. This information does not take the place of talking with your healthcare provider

about your medical condition or your treatment.

What is the most important information I should know about SPORANOX?

SPORANOX can cause serious side effects, including:

1. Heart failure. Do not take SPORANOX if you have had heart failure, including congestive heart failure.

Stop taking SPORANOX and call your healthcare provider right away if you have any of these symptoms

of congestive heart failure:

• shortness of breath

• swelling of your feet, ankles or legs

• sudden weight gain

• increased tiredness

• coughing up white or pink mucus (phlegm)

• fast heartbeat

• waking up at night more than normal for you

2. Heart problems and other serious medical problems. Serious medical problems that affect the heart and

other parts of your body can happen if you take SPORANOX with certain other medicines. Do not take

SPORANOX if you also take the following medicines:

• 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

• venetoclax (see below)

• finerenone

• voclosporin

Do not take SPORANOX with venetoclax for chronic lymphocytic leukemia/small lymphocytic lymphoma when

you first start treatment with venetoclax or with increasing doses of venetoclax.

This is not a complete list of medicines that can interact with SPORANOX. SPORANOX may affect the way other

medicines work, and other medicines may affect how SPORANOX works. You can ask your pharmacist for a list

of medicines that interact with SPORANOX.

Before you start taking SPORANOX, tell your healthcare provider about all the medicines you take, including

prescription and over-the-counter medicines, vitamins, and herbal supplements.

Before you start any new medicine, ask your healthcare provider or pharmacist if it is safe to take it with

SPORANOX.

3. Liver problems. SPORANOX can cause serious liver problems which may be severe and lead to death. Stop

taking SPORANOX and call your healthcare provider right away if you have any of these symptoms of

liver problems:

• tiredness

• loss of appetite for several days or longer

• nausea or vomiting

• dark or “tea-colored” urine

• your skin or the white part of your eyes turn yellow

(jaundice)

• light-colored stools (bowel movement)

For more information about side effects, see “What are the possible side effects of SPORANOX?”

What is SPORANOX?

• SPORANOX is a prescription medicine used to treat the following fungal infections of the toenails, fingernails

and other parts of the body: blastomycosis, histoplasmosis, aspergillosis, and onychomycosis.

• It is not known if SPORANOX is safe and effective in children.

Do not take SPORANOX if you:

• have or have had heart failure, including congestive heart failure.

• take certain medicines. See “What is the most important information I should know about SPORANOX?”

• are pregnant or plan to become pregnant. SPORANOX can harm your unborn baby. Tell your healthcare

provider right away if you become pregnant while taking SPORANOX. Females who are able to become

pregnant must use effective forms of birth control during treatment and for 2 months after stopping treatment with

SPORANOX.

• are allergic to itraconazole or any of the ingredients in SPORANOX. See the end of this Patient Information

leaflet for a complete list of ingredients in SPORANOX.

Before taking SPORANOX, tell your healthcare provider about all of your medical conditions, including if

you:

• have heart problems.

• have liver problems.

• have kidney problems.

• have a weakened immune system (immunocompromised).

• have lung problems including cystic fibrosis.

• are breastfeeding or plan to breastfeed. SPORANOX can pass into your breast milk. You and your healthcare

provider should decide if you will take SPORANOX or breastfeed.

Taking SPORANOX with certain medicines may affect each other. Taking SPORANOX with other medicines can

cause serious side effects.

How should I take SPORANOX?

• Take SPORANOX exactly as prescribed by your healthcare provider. Your healthcare provider will tell you how

much SPORANOX to take and when to take it.

• You will receive SPORANOX capsules in a blister pack or bottle. Your healthcare provider will decide the type of

SPORANOX that is right for you.

• Take SPORANOX with a full meal.

• Swallow SPORANOX capsules whole.

• You should not take SPORANOX oral solution instead of SPORANOX capsules, because they will not work the

same way.

• If you take too much SPORANOX, call your healthcare provider or go to the nearest hospital emergency room

right away.

What should I avoid while taking SPORANOX?

SPORANOX can cause dizziness and vision problems. Do not drive or operate machinery until you know how

SPORANOX affects you.

What are the possible side effects of SPORANOX?

SPORANOX may cause serious side effects, including:

• See “What is the most important information I should know about SPORANOX?”

• Nerve problems (neuropathy). Call your healthcare provider right away if you have tingling or numbness in

your hands or feet. Your healthcare provider may stop your treatment with SPORANOX if you have nerve

problems.

• Hearing loss. Hearing loss can happen for a short time or permanently in some people who take SPORANOX.

Stop taking SPORANOX and call your healthcare provider right away if you have any changes in your hearing.

The most common side effects of SPORANOX include: headache, rash, digestive system problems (such as

nausea and vomiting), and edema.

Additional possible side effects include upset stomach, 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 possible side effects of SPORANOX.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store SPORANOX?

• Store SPORANOX at room temperature between 59°F to 77°F (15°C to 25°C).

• Keep SPORANOX dry and away from light.

Keep SPORANOX and all medicines out of the reach of children.

General information about the safe and effective use of SPORANOX.

Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use

SPORANOX for a condition for which it was not prescribed. Do not give SPORANOX to other people, even if they

have the same symptoms that you have. It may harm them.

You can ask your doctor or pharmacist for information about SPORANOX that is written for health professionals.

What are the ingredients in SPORANOX?

Active ingredients: itraconazole

Inactive ingredients: hard gelatin capsule, hypromellose, polyethylene glycol (PEG) 20,000, titanium dioxide, FD&C

Blue No. 1, FD&C Blue No. 2, D&C Red No. 22 and D&C Red No. 28.

Manufactured for: Janssen Pharmaceuticals, Inc. Titusville, NJ 08560, USA

For more information or call 1-800-526-7736.

This Patient Information has been approved by the U.S. Food and Drug Administration Revised: 10/2023

cp-59756v9