Public Health Service
`Food and Drug Administration
`Rockville, MD 20857
`
`
`
`DEPARTMENT OF HEALTH & HUMAN SERVICES
`
`
`
`
`
`
`NDA 20-083/S-034, S035
`
`
`
`Johnson & Johnson Pharmaceutical Research and Development, L.L.C.
`Attention: Kathleen F. Dusek, R. Ph., RAC
`
` Associate Director, Regulatory Affairs
`1125 Trenton-Harbourton Road
`Titusville, NJ 08560-0200
`
`
`
`Dear Ms. Dusek:
`
`Please refer to your supplemental new drug applications dated January 14, 2004 and January 23, 2004
`received January 15, 2004 and January 26, 2004, respectively, submitted under section 505(b) of the
`Federal Food, Drug, and Cosmetic Act for Sporanox® (itraconazole) Capsules, 100 mg.
`
`We acknowledge receipt of your submissions dated January 21, 2004, March 24, 2004, and July 1,
`2004.
`
`These “Changes Being Effected in 30 days” supplemental new drug applications provide for the
`following revisions to the Sporanox® Capsule package insert (PI) and patient package insert (PPI):
`
`Added text = double underline and Deleted text = strikethrough
`
`
`1. BOX WARNING
`• Levacetylmethadol is added as a contraindicated drug with Sporanox® in the Drug
`Interactions subsection to read:
`
`
`
`
`
`Drug Interactions: Coadministration of cisapride, pimozide, quinidine,
`dofetilide, or levacetylmethadol (levomethadyl) with SPORANOX®
`(itraconazole) Capsules, Injection or Oral Solution is contraindicated.
`SPORANOX®, a potent cytochrome P450 3A4 isoenzyme system (CYP3A4)
`inhibitor, may increase plasma concentrations of drugs metabolized by this
`pathway. Serious cardiovascular events, including QT prolongation, torsades de
`pointes, ventricular tachycardia, cardiac arrest, and/or sudden death have occurred
`in patients using cisapride, pimozide, levacetylmethadol (levomethadyl), or quinidine
`concomitantly with SPORANOX® and/or other CYP3A4 inhibitors.
`See CONTRAINDICATIONS, WARNINGS, and PRECAUTIONS: Drug
`Interactions for more information.
`
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`2. CONTRAINDICATIONS
`• Levacetylmethadol and ergot alkaloids are added as contraindicated drugs with Sporanox® in
`the Drug Interactions subsection to read:
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`NDA 20-083/S-034, S-035
`Page 2
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`Drug Interactions: Concomitant administration of SPORANOX (itraconazole)
`Capsules, Injection, or Oral Solution and certain drugs metabolized by the
`cytochrome P450 3A4 isoenzyme system (CYP3A4) may result in increased
`plasma concentrations of those drugs, leading to potentially serious and/or
`life-threatening adverse events. Cisapride, oral midazolam, pimozide, quinidine,
`dofetilide, triazolam and levacetylmethadol (levomethadyl) are contraindicated
`with SPORANOX. HMG CoA-reductase inhibitors metabolized by CYP3A4,
`such as lovastatin and simvastatin, are also contraindicated with SPORANOX.
`Ergot alkaloids metabolized by CYP3A4 such as dihydroergotamine, ergometrine
`(ergonovine), ergotamine and methylergometrine (methylergonovine) are
`contraindicated with SPORANOX. (See BOX WARNING, and
`PRECAUTIONS: Drug Interactions.)
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`3. WARNINGS
`• Levacetylmethadol is added as a contraindicated drug with Sporanox® in the
`Cardiac Dysrhythmias subsection to read:
`
`
`
`Cardiac Dysrhythmias: Life-threatening cardiac dysrhythmias and/or sudden
`death have occurred in patients using cisapride, pimozide, levacetylmethadol
`(levomethadyl), or quinidine concomitantly with SPORANOX® and/or other
`CYP3A4 inhibitors.
`
`
`
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`
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`4. PRECAUTIONS
`• Addition of disopyramide, halofantrine, budesonide, dexamethasone, cilostazol and eletriptan
`to Table 1 in the Drug Interactions:
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`NDA 20-083/S-034, S-035
`Page 3
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`Table 1. Selected Drugs that are predicted to alter the plasma concentration of
`itraconazole or have their plasma concentration altered by SPORANOX1
`Drug plasma concentration increased by itraconazole
`digoxin, dofetilide2, quinidine2, disopyramide
`Antiarrhythmics
`Anticoagulants
`warfarin
`Anticonvulsants
`carbamazepine
`Antimycobacterials
`rifabutin
`Antineoplastics
`busulfan, docetaxel, vinca alkaloids
`pimozide2,
`Antipsychotics
`alprazolam, diazepam, midazolam,2,3 triazolam2
`Benzodiazepines
`Calcium Channel Blockers
`dihydropyridines, verapamil
`Gastrointestinal Motility
`cisapride2
`Agents
`HMG CoA-Reductase
`Inhibitors
`Immunosuppressants
`Oral Hypoglycemics
`Protease Inhibitors
`Other
`
`atorvastatin, cerivastatin, lovastatin,2 simvastatin2
`cyclosporine, tacrolimus, sirolimus
`oral hypoglycemics
`indinavir, ritonavir, saquinavir
`levacetylmethadol (levomethadyl), ergot alkaloids,
`halofantrine, alfentanil, buspirone, methylprednisolone,
`budesonide, dexamethasone, trimetrexate, warfarin,
`cilostazol, eletriptan
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`Decrease plasma concentration of itraconazole
`carbamazepine, phenobarbital, phenytoin
`isoniazid, rifabutin, rifampin
`antacids, H2-receptor antagonists, proton pump inhibitors
`
`Anticonvulsants
`Antimycobacterials
`Gastric Acid
`Suppressors/Neutralizers
`Non-nucleoside Reverse
`Transcriptase Inhibitors
`
`nevirapine
`
`Increase plasma concentration of itraconazole
`Macrolide Antibiotics
`clarithromycin, erythromycin
`Protease Inhibitors
`indinavir, ritonavir
`
`• The following statement regarding concomitant use of disopyramide with Sporanox is added to
`Antiarrhythmics subsection:
`
`The class IA antiarrhythmic disopyramide has the potential to increase the
`QT interval at high plasma concentrations. Caution is advised when
`SPORANOX and disopyramide are administered concomitantly.
`
`• New information is added in the PRECAUTIONS: Other subsection to read:
`
`
`Other:
`• Levacetylmethadol (levomethadyl) is known to prolong the QT interval and is
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`metabolized by CYP3A4. Co-administration of levacetylmethadol with SPORANOX
`could result in serious cardiovascular events.Therefore, concomitant administration of
`SPORANOX and levacetylmethadol is contraindicated.
`• Elevated concentrations of ergot alkaloids can cause ergotism, ie. a risk for vasospasm
`potentially leading to cerebral ischemia and/or ischemia of the extremities.
`Concomitant administration of ergot alkaloids such as dihydroergotamine, ergometrine
`(ergonovine), ergotamine and methylergometrine (methylergonovine) with
`SPORANOX is contraindicated.
`• Halofantrine has the potential to prolong the QT interval at high plasma concentrations.
`Caution is advised when SPORANOX and halofantrine are administered
`concomitantly.
`In vitro data suggest that alfentanil is metabolized by CYP3A4. Administration with
`SPORANOX may increase plasma concentrations of alfentanil.
`• Human pharmacokinetic data suggest that concomitant administration of SPORANOX
`and buspirone results in significant increases in plasma concentrations of buspirone.
`• SPORANOX may inhibit the metabolism of methylprednisolone.certain
`glucocorticosteroids such as budesonide, dexamethasone and methylprednisolone.
`In vitro data suggest that trimetrexate is extensively metabolized by CYP3A4. In vitro
`animal models have demonstrated that ketoconazole potently inhibits the metabolism of
`trimetrexate. Although there are no data regarding the effect of itraconazole on
`trimetrexate metabolism, because of the similarities between ketoconazole and
`itraconazole, concomitant administration of SPORANOX and trimetrexate may inhibit
`the metabolism of trimetrexate.
`• SPORANOX enhances the anticoagulant effect of coumarin-like drugs, such as
`warfarin.
`• Cilostazol and eletriptan are CYP3A4 metabolized drugs that should be used with
`caution when co-administered with SPORANOX.
`
`•
`
`•
`
`
`• The following statement is added to the Pregnancy: Teratogenic Effects. Pregnancy
`Category C subsection:
`
`During post-marketing experience, cases of congenital abnormalities have been
`reported. (See ADVERSE REACTIONS, Post-marketing Experience.)
`
`
`
`
`5. ADVERSE REACTIONS
`• Addition of anaphylactic, anaphylactoid and allergic reactions and a statement regarding cases
`of congenital abnormalities to the Post-marketing Experience subsection to read:
`
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`Post-marketing Experience:
`Worldwide post-marketing experiences with the use of SPORANOX include adverse events
`of gastrointestinal origin, such as dyspepsia, nausea, vomiting, diarrhea, abdominal pain and
`constipation. Other reported adverse events include peripheral edema, congestive heart failure
`and pulmonary edema, headache, dizziness, peripheral neuropathy, menstrual disorders,
`reversible increases in hepatic enzymes, hepatitis, liver failure, hypokalemia,
`hypertriglyceridemia, alopecia, allergic reactions (such as pruritus, rash, urticaria, angioedema,
`anaphylaxis), Stevens-Johnson syndrome, anaphylactic, anaphylactoid and allergic reactions,
`photosensitivity and neutropenia. There is limited information on the use of SPORANOX
`during pregnancy. Cases of congenital abnormalities including skeletal, genitourinary tract,
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`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).
`
`
`
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`
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`6. Patient Package Insert (PPI)
`• The following sections of the PPI were revised to include levacetylmethadol and the ergot
`alkaloids as drugs contraindicated for use with Sporanox:
`
`
`
`Never take SPORANOX® if you:
`are taking any of the medicines listed below. Dangerous or even
`•
`
`life-threatening abnormal heartbeats could result:
`quinidine (such as Cardioquin®, Quinaglute®, Quinidex®)
`•
`dofetilide (such as Tikosyn)
`•
`cisapride (such as Propulsid®)
`•
`• pimozide (such as Orap®)
`• levacetylmethadol (such as Orlaam®)
`
`are taking any of the following medicines:
`lovastatin (such as Mevacor®,Advicor™, Altocor™)
`•
`simvastatin (such as Zocor®)
`•
`triazolam (such as Halcion®)
`•
`midazolam (such as Versed®)
`•
`ergot alkaloids (such as Migranal®, Ergonovine, Cafergot®, Methergine®)
`•
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`•
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`The following are registered trademarks of their respective manufacturers:
`Mevacor® (Merck & Co., Inc.), AdvicorTM (Kos Pharmaceuticals, Inc.), Altocor™
`(Andrx Laboratories), Zocor® (Merck & Co., Inc.), Halcion® (Pharmacia), Versed® (Roche
`Pharmaceuticals), Cardioquin® (The Purdue Frederick Company), Quinaglute® (Berlex
`Laboratories), Quinidex® (A.H. Robins), TikosynTM (Pfizer, Inc.), Propulsid® (Janssen
`Pharmaceutica Products, L.P.), Orlaam® (Roxane Laboratories), Migranal® (Xcel
`Pharmaceuticals), Ergonovine (PDRX Pharmaceuticals), Cafergot® (Novartis Pharmaceuticals
`Corporation), Methergine®(Novartis Pharmaceuticals Corporation) and Orap® (Gate
`Pharmaceuticals)
`
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`We completed our review of these applications, as amended. These applications are approved,
`effective on the date of this letter, for use as recommended in the agreed-upon enclosed labeling text.
`Accordingly, these supplemental applications are approved on the date of this letter.
`
`The final printed labeling (FPL) must be identical to the enclosed labeling (text for the package insert
`submitted on January 21, 2004 and text for the patient package insert submitted on January 23, 2004).
`
`The electronic labeling rule published December 11, 2003, (68 FR 69009) requires submission of
`labeling content in electronic format effective June 8, 2004. For additional information, consult the
`following guidances for industry regarding electronic submissions: Providing Regulatory Submissions
`in Electronic Format - NDAs (January 1999) and Providing Regulatory Submissions in Electronic
`Format – Content of Labeling (February 2004). The guidances specify that labeling to be submitted
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`NDA 20-083/S-034, S-035
`Page 6
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`in pdf format. To assist in our review of the FPL and future submission, we request that labeling also
`be submitted in MS Word format. If formatted copies of all labeling pieces (i.e., package insert,
`patient package insert, container labels, and carton labels) are submitted electronically, labeling does
`not need to be submitted in paper. For administrative purposes, this submission should be designated
`"FPL for approved supplements NDA 20-083/S-034, S-035.” Approval of this submission by FDA
`is not required before the labeling is used.
`
`If you issue a letter communicating important information about this drug product (i.e., a “Dear Health
`Care Professional” letter), we request that you submit a copy of the letter to this NDA and a copy to
`the following address:
`
`MEDWATCH, HFD-410
`FDA
`5600 Fishers Lane
`Rockville, MD 20857
`
`
`
`
`
`We remind you that you must comply with reporting requirements for an approved NDA (21 CFR
`314.80 and 314.81).
`
`If you have any questions, call Yon Yu, Pharm D., Regulatory Project Manager, at (301) 827-2127.
`
`Sincerely,
`
`{See appended electronic signature page}
`
`Renata Albrecht, M.D.
`Director
`Division of Special Pathogen and Immunologic
`
`Drug Products
`Office of Drug Evaluation IV
`Center for Drug Evaluation and Research
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`---------------------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`---------------------------------------------------------------------------------------------------------------------
` /s/
`---------------------
`Renata Albrecht
`7/14/04 06:29:09 PM
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`CBE-January 2004
`
`
`
`1
`
`JANSSEN
`PHARMACEUTICA
`PRODUCTS, L.P.
`
`SPORANOX
`(ITRACONAZOLE)
` CAPSULES
`
`
`
`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. 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 CLINICAL PHARMACOLOGY: Special
`Populations, CONTRAINDICATIONS, WARNINGS, PRECAUTIONS: Drug
`Interactions and ADVERSE REACTIONS: Post-marketing Experience for more
`information.)
`
`Drug Interactions: Coadministration of cisapride, pimozide, quinidine,
`dofetilide, or levacetylmethadol (levomethadyl) with SPORANOX®
`(itraconazole) Capsules, Injection or Oral Solution is contraindicated.
`SPORANOX®, a potent cytochrome P450 3A4 isoenzyme system (CYP3A4)
`inhibitor, may increase plasma concentrations of drugs metabolized by this
`pathway. Serious cardiovascular events, including QT prolongation, torsades de
`pointes, ventricular tachycardia, cardiac arrest, and/or sudden death have
`occurred in patients using cisapride, pimozide, levacetylmethadol (levomethadyl),
`or quinidine concomitantly with SPORANOX® and/or other CYP3A4 inhibitors.
`See CONTRAINDICATIONS, WARNINGS, and PRECAUTIONS: Drug
`Interactions for more information.
`
`DESCRIPTION
`
`SPORANOX® is the brand name for itraconazole, a synthetic triazole 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:
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`CBE-January 2004
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`
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`2
`
`(insert structure)
`
`(±)-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]-∆2-1,2,4-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]-∆2-
`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]-∆2-1,2,4-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.
`Inactive ingredients are gelatin, hydroxypropyl methylcellulose, polyethylene glycol
`(PEG) 20,000, starch, sucrose, 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: NOTE: The plasma concentrations reported
`below were measured by high-performance liquid chromatography (HPLC) specific for
`itraconazole. When itraconazole in plasma is measured by a bioassay, values reported
`are approximately 3.3 times higher than those obtained by HPLC due to the presence of
`the bioactive metabolite, hydroxyitraconazole. (See MICROBIOLOGY.)
`
`The pharmacokinetics of itraconazole after intravenous administration and its absolute
`oral bioavailability from an oral solution were studied in a randomized crossover study in
`6 healthy male volunteers. The observed absolute oral bioavailability of itraconazole
`was 55%.
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`CBE-January 2004
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`3
`
`The oral bioavailability of itraconazole is maximal when SPORANOX® (itraconazole)
`Capsules are taken with a full meal. The pharmacokinetics of itraconazole were studied
`in 6 healthy male volunteers who received, in a crossover design, single 100-mg doses
`of itraconazole as a polyethylene glycol capsule, with or without a full meal. The same 6
`volunteers also received 50 mg or 200 mg with a full meal in a crossover design. In this
`study, only itraconazole plasma concentrations were measured. The respective
`pharmacokinetic parameters for itraconazole are presented in the table below:
`
`
`
`Cmax
`(ng/mL)
`
`Tmax
`(hours)
`
`AUC0-∞
`(ng·h/mL)
`
`50 mg
`(fed)
`
`100 mg
`(fed)
`
`45 ± 16*
`
`132 ± 67
`
`100 mg
`(fasted)
`
`38 ± 20
`
`200 mg
`(fed)
`
`289 ± 100
`
`3.2 ± 1.3
`
`4.0 ± 1.1
`
`3.3 ± 1.0
`
`4.7 ± 1.4
`
`567 ± 264 1899 ± 838
`
`722 ± 289 5211 ± 2116
`
`*mean + standard deviation
`Doubling the SPORANOX® dose results in approximately a three-fold increase in the
`itraconazole plasma concentrations.
`
`Values given in the table below represent data from a crossover pharmacokinetics study
`in which 27 healthy male volunteers each took a single 200-mg dose of SPORANOX®
`Capsules with or without a full meal:
`
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`CBE-January 2004
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`4
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`Itraconazole
`
`Hydroxyitraconazole
`
`Fed
`
`Fasted
`
`Fed
`
`Fasted
`
`239 ± 85*
`
`140 ± 65
`
`397 ± 103
`
`286 ± 101
`
`4.5 ± 1.1
`
`3.9 ± 1.0
`
`5.1 ± 1.6
`
`4.5 ± 1.1
`
`3423 ± 1154
`
`2094 ± 905
`
`7978 ± 2648
`
`5191 ± 2489
`
`
`
`
`
`Cmax
`(ng/mL)
`
`Tmax
`(hours)
`
`AUC0-∞
`(ng·h/mL)
`
`t1/2 (hours)
`
`21 ± 5
`
`21 ± 7
`
`12 ± 3
`
`12 ± 3
`
`*mean ± standard deviation
`
`
`Absorption of itraconazole under fasted conditions in individuals with relative or absolute
`achlorhydria, such as patients with AIDS or volunteers taking gastric acid secretion
`suppressors (e.g., H2 receptor antagonists), was increased when SPORANOX®
`Capsules were administered with a cola beverage. Eighteen men with AIDS received
`single 200-mg doses of SPORANOX® Capsules under fasted conditions with 8 ounces
`of water or 8 ounces of a cola beverage in a crossover design. The absorption of
`itraconazole was increased when SPORANOX® Capsules were coadministered with a
`cola beverage, with AUC0-24 and Cmax increasing 75% ± 121% and 95% ± 128%,
`respectively.
`Thirty healthy men received single 200-mg doses of SPORANOX® Capsules under
`fasted conditions either 1) with water; 2) with water, after ranitidine 150 mg b.i.d. for 3
`days; or 3) with cola, after ranitidine 150 mg b.i.d. for 3 days. When SPORANOX®
`Capsules were administered after ranitidine pretreatment, itraconazole was absorbed to
`a lesser extent than when SPORANOX® Capsules were administered alone, with
`decreases in AUC0-24 and Cmax of 39% ± 37% and 42% ± 39%, respectively. When
`SPORANOX® Capsules were administered with cola after ranitidine pretreatment,
`itraconazole absorption was comparable to that observed when SPORANOX® Capsules
`were administered alone. (See PRECAUTIONS: Drug Interactions.)
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`CBE-January 2004
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`5
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`
`Steady-state concentrations were reached within 15 days following oral doses of 50 mg
`to 400 mg daily. Values given in the table below are data at steady-state from a
`pharmacokinetics study in which 27 healthy male volunteers took 200-mg SPORANOX®
`Capsules b.i.d.(with a full meal) for 15 days:
`
`
`
`
`Cmax (ng/mL)
`
`Cmin (ng/mL)
`
`Tmax (hours)
`
`AUC0-12 h
`(ng·h/mL)
`
`t1/2 (hours)
`
`Itraconazole
`
`2282 ± 514*
`
`1855 ± 535
`
`4.6 ± 1.8
`
`22569 ± 5375
`
`Hydroxyitraconazole
`
`3488 ± 742
`
`3349 ± 761
`
`3.4 ± 3.4
`
`38572 ± 8450
`
`64 ± 32
`
`56 ± 24
`
`*mean ± standard deviation
`The plasma protein binding of itraconazole is 99.8% and that of hydroxyitraconazole is
`99.5%. Following intravenous administration, the volume of distribution of itraconazole
`averaged 796 ± 185 liters.
`
`Itraconazole is metabolized predominately by the cytochrome P450 3A4 isoenzyme
`system (CYP3A4), resulting in the formation of several metabolites, including
`hydroxyitraconazole, the major metabolite. Results of a pharmacokinetics study suggest
`that itraconazole may undergo saturable metabolism with multiple dosing. Fecal
`excretion of the parent drug varies between 3-18% of the dose. Renal excretion of the
`parent drug is less than 0.03% of the dose. About 40% of the dose is excreted as
`inactive metabolites in the urine. No single excreted metabolite represents more than
`5% of a dose. Itraconazole total plasma clearance averaged 381 ± 95 mL/minute
`following intravenous administration. (See CONTRAINDICATIONS and
`PRECAUTIONS: Drug Interactions for more information.)
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`Special Populations:
`Renal Insufficiency: A pharmacokinetic study using a single 200-mg dose of
`itraconazole (four 50-mg capsules) 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. x 1.73 m2, the bioavailability 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 AUC0-8). Plasma concentration-versus-time profiles
`showed wide intersubject variation in all three groups.
`
`
`
`Hepatic Insufficiency: A pharmacokinetic study using a single 100-mg dose of
`itraconazole (one 100-mg capsule) was conducted in 6 healthy and 12 cirrhotic subjects.
`No statistically significant differences in AUC were seen between these two groups. A
`statistically significant reduction in mean Cmax (47%) and a twofold increase in the
`elimination half-life (37 ± 17 hours) of itraconazole were noted in cirrhotic subjects
`compared with healthy subjects. Patients with impaired hepatic function should be
`carefully monitored when taking itraconazole. The prolonged elimination half-life of
`itraconazole observed in cirrhotic patients should be considered when deciding to initiate
`therapy with other medications metabolized by CYP3A4. (See BOX WARNING,
`CONTRAINDICATIONS, and PRECAUTIONS: Drug Interactions.)
`
`
`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 SPORANOX Injection (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 CONTRAINDICATIONS,
`WARNINGS, PRECAUTIONS: Drug Interactions and ADVERSE REACTIONS: Post-
`marketing Experience for more information.)
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`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 Vivo: Itraconazole exhibits in vitro activity against Blastomyces
`dermatitidis, Histoplasma capsulatum, Histoplasma duboisii, Aspergillus flavus,
`Aspergillus fumigatus, Candida albicans, and Cryptococcus neoformans. Itraconazole
`also exhibits varying in vitro activity against Sporothrix schenckii, Trichophyton species,
`Candida krusei, and other Candida species. The bioactive metabolite,
`hydroxyitraconazole, has not been evaluated against Histoplasma capsulatum and
`Blastomyces dermatitidis. Correlation between minimum inhibitory concentration (MIC)
`results in vitro and clinical outcome has yet to be established for azole antifungal agents.
`
`Itraconazole administered orally was active in a variety of animal models of fungal
`infection using standard laboratory strains of fungi. Fungistatic activity has been
`demonstrated against disseminated fungal infections caused by Blastomyces
`dermatitidis, Histoplasma duboisii, Aspergillus fumigatus, Coccidioides immitis,
`Cryptococcus neoformans, Paracoccidioides brasiliensis, Sporothrix schenckii,
`Trichophyton rubrum, and Trichophyton mentagrophytes.
`
`Itraconazole administered at 2.5 mg/kg and 5 mg/kg via the oral and parenteral routes
`increased survival rates and sterilized organ systems in normal and immunosuppressed
`guinea pigs with disseminated Aspergillus fumigatus infections. Oral itraconazole
`administered daily at 40 mg/kg and 80 mg/kg increased survival rates in normal rabbits
`with disseminated disease and in immunosuppressed rats with pulmonary Aspergillus
`fumigatus infection, respectively. Itraconazole has demonstrated antifungal activity in a
`variety of animal models infected with Candida albicans and other Candida species.
`
`Resistance: Isolates from several fungal species with decreased susceptibility to
`itraconazole have been isolated in vitro and from patients receiving prolonged therapy.
`
`Several in vitro studies have reported that some fungal clinical isolates, including
`Candida species, with reduced susceptibility to one azole antifungal agent may also be
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`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. The
`relevance of these in vitro susceptibility data to clinical outcome remains to be
`elucidated.
`
`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:
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`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.
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`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