SPORANOX®
`
`
` (itraconazole)
`
` Capsules
` BOXED WARNING
`
`
`
`
` Congestive Heart Failure, Cardiac Effects and Drug Interactions:
`
`
`
`
` 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 the following drugs are contraindicated with
`
`
`
`
` SPORANOX® Capsules: methadone, disopyramide, dofetilide, dronedarone, quinidine,
`
`
`
` ergot alkaloids (such as dihydroergotamine, ergometrine (ergonovine), ergotamine,
`
`
` methylergometrine (methylergonovine)), irinotecan, lurasidone, oral midazolam, pimozide,
`
`triazolam, felodipine, nisoldipine, ranolazine, eplerenone, cisapride, lovastatin, simvastatin,
`
`
`
` ticagrelor and, in subjects with varying degrees of renal or hepatic impairment, colchicine,
` fesoterodine, telithromycin and solifenacin. 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
`
` and
`
`
` arrhythmia.
` See CONTRAINDICATIONS
`and WARNINGS
`Sections,
` 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:
`
`
`
`
`
`Reference ID: 3733660
`
`
`
` 1
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`Teva Pharmaceuticals USA, Inc. v. Corcept Therapeutics, Inc.
`PGR2019-00048
`Corcept Ex. 2018, Page 1
`
`

`

`
`
`(±)-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]-Δ2-1,2,4-triazolin-5-one
`
`(±)-1-[(R*)-sec-butyl]-4-[p-[4-[p-[[(2S*,4R*)-2-(2,4-dichlorophenyl)-2-(1H­
`mixture with
`1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1-piperazinyl]phenyl]-Δ2-1,2,4­
`
` triazolin-5-one
`
`
`
` or
`
`(±)-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]-Δ2-1,2,4-triazolin-5-one
`
`
`Itraconazole has a molecular formula of C35H38Cl2N8O4 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.
`
`
`
`
`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 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 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
`
`
`
`
`
`Reference ID: 3733660
`
`
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`Teva Pharmaceuticals USA, Inc. v. Corcept Therapeutics, Inc.
`PGR2019-00048
`Corcept Ex. 2018, Page 2
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` 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., H2-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 H2-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.
`
`
`
`Reference ID: 3733660
`
`
`
` 3
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`Teva Pharmaceuticals USA, Inc. v. Corcept Therapeutics, Inc.
`PGR2019-00048
`Corcept Ex. 2018, Page 3
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`

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` 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 m2, the exposure, based on AUC, was slightly reduced compared with normal
`
`
`
`
`population parameters. This study did not demonstrate any significant effect of hemodialysis or
`continuous ambulatory peritoneal dialysis on the pharmacokinetics of itraconazole (Tmax, Cmax,
`
`
`and AUC0-8h). 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 Cmax (47%) and a
`
`
`
`twofold increase in the elimination half-life (37 ± 17 hours vs. 16 ± 5 hours) of itraconazole
`
`were noted in cirrhotic subjects compared with healthy subjects. However, overall exposure to
`
`
`
`Reference ID: 3733660
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`
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`Teva Pharmaceuticals USA, Inc. v. Corcept Therapeutics, Inc.
`PGR2019-00048
`Corcept Ex. 2018, Page 4
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` itraconazole, based on AUC, was similar in cirrhotic patients and in healthy subjects. Data are
`
`
`(See
` during
`long-term
` use
`of
`
`itraconazole.
`
`
`not available
`in cirrhotic patients
`AND
` and
`
`ONS: Drug
`
`Interactions
`DOSAGE
`
`
`
` CONTRAINDICATIONS, PRECAUTI
`
` 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.
`
`
`
`Activity In Vitro and in Clinical Infections:
`in vitro activity against Blastomyces dermatitidis, Histoplasma
`
`
`Itraconazole exhibits
`
`capsulatum, Histoplasma duboisii, Aspergillus flavus, Aspergillus fumigatus, and Trichophyton
`
`
`
`
`
`
`species (See INDICATIONS AND USAGE, Description of Clinical Studies).
`
`Correlation between minimum inhibitory concentration (MIC) results in vitro and clinical
`
`
`
`
`
`
`outcome has yet to be established for azole antifungal agents.
`
`
`Drug 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
`
`
`
`Reference ID: 3733660
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`
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` 5
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`Teva Pharmaceuticals USA, Inc. v. Corcept Therapeutics, Inc.
`PGR2019-00048
`Corcept Ex. 2018, Page 5
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` 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
`14C-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).
`
`
`
`laboratory
`for
`specimens
`treatment, appropriate nail
`initiating
`to
`Prior
`testing
`
`(KOH preparation, fungal culture, or nail biopsy) should be obtained to confirm the diagnosis
`
`
`of onychomycosis.
`
`
`
`
`Reference ID: 3733660
`
`
`
` 6
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`Teva Pharmaceuticals USA, Inc. v. Corcept Therapeutics, Inc.
`PGR2019-00048
`Corcept Ex. 2018, Page 6
`
`

`

`CONTRAINDICATIONS,
`(See
`
`
`
` CLINICAL PHARMACOLOGY: Special Populations,
`
`
` 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.
`
`
`
`
`
`
`Reference ID: 3733660
`
`
`
` 7
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`Teva Pharmaceuticals USA, Inc. v. Corcept Therapeutics, Inc.
`PGR2019-00048
`Corcept Ex. 2018, Page 7
`
`

`

` 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® .
`
`Plasma concentrations increase for the following drugs: methadone, disopyramide, dofetilide,
`
`
`
`
`
`
`dronedarone, quinidine, ergot alkaloids (such as dihydroergotamine, ergometrine (ergonovine),
`
`
`ergotamine, methylergometrine (methylergonovine)), irinotecan, lurasidone, oral midazolam,
`
`
`pimozide, triazolam, felodipine, nisoldipine, ranolazine, eplerenone, cisapride, lovastatin,
`
`simvastatin, ticagrelor, and, in subjects with varying degrees of renal or hepatic impairment,
`
`
`
`telithromycin and solifenacin. (See PRECAUTIONS: Drug
`colchicine, fesoterodine,
`
`
`
`
`
`Reference ID: 3733660
`
`
`
` 8
`
`Teva Pharmaceuticals USA, Inc. v. Corcept Therapeutics, Inc.
`PGR2019-00048
`Corcept Ex. 2018, Page 8
`
`

`

`
`
`
` Interactions Section for specific examples.) This increase in drug concentrations caused by
`
` coadministration with itraconazole may increase or prolong both the pharmacologic effect
`
` 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. Specific examples are listed in
`
`
`
`
` PRECAUTIONS: Drug Interactions.
`
`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®
`
`
`inhibitors. Concomitant administration of
`and/or other CYP3A4
`these drugs with
`SPORANOX® is 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
`
`
`
`
`
`
`
`Reference ID: 3733660
`
`
`
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`

`

`
`
` 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
`
`Populations,
`infections.
`(See
`CLINICAL
`PHARMACOLOGY:
`Special
`and ADVERSE
`Interactions,
`PRECAUTIONS: Drug
`CONTRAINDICATIONS,
`
`
`
`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.
`
`
`
`Reference ID: 3733660
`
`
`
` 10
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`Corcept Ex. 2018, Page 10
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`

`
` 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.
`
`
`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
`
`
`
`Reference ID: 3733660
`
`
`
` 11
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`
`

`

`
`
`
`
` 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.
`
`taking any concomitant
`their physician before
`Instruct patients
`to contact
`
`
`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:
`
`
`
`Itraconazole is mainly metabolized through CYP3A4. Other drugs that either share this
`
`
`
`metabolic pathway or modify CYP3A4 activity may influence the pharmacokinetics of
`
`
`
`
`itraconazole. Similarly, itraconazole may modify the pharmacokinetics of other drugs that
`
`share this metabolic pathway. Itraconazole is a potent CYP3A4 inhibitor and a P-glycoprotein
`
`
`
`inhibitor. When using concomitant medication, it is recommended that the corresponding label
`
`
`be consulted for information on the route of metabolism and the possible need to adjust
`
`dosages.
`
`
`
`Drugs that may decrease itraconazole plasma concentrations
`
`
`
`
`Drugs that reduce the gastric acidity (e.g. acid neutralizing medicines such as aluminum
`hydroxide, or acid secretion suppressors such as H2-receptor antagonists and proton pump
`
`
`
`Reference ID: 3733660
`
`
`
` 12
`
`Teva Pharmac