itraconazole
Dosage Form: oral solution
Sporanox®
(itraconazole)
Oral Solution
Congestive Heart Failure
When itraconazole was administered intravenously to dogs and healthy human volunteers, negative inotropic effects were seen. If signs or symptoms of congestive heart failure occur during administration of Sporanox® (itraconazole) Oral Solution, continued Sporanox® use should be reassessed. (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 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.)
Sporanox 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:
(±) - 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 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] - 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® (itraconazole) Oral Solution contains 10 mg of itraconazole per mL, solubilized by hydroxypropyl-β-cyclodextrin (400 mg/mL) as a molecular inclusion complex. Sporanox® Oral Solution is clear and yellowish in color with a target pH of 2. Other ingredients are hydrochloric acid, propylene glycol, purified water, sodium hydroxide, sodium saccharin, sorbitol, cherry flavor 1, cherry flavor 2 and caramel flavor.
Sporanox - 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 may be higher than those obtained by HPLC due to the presence of the bioactive metabolite, hydroxyitraconazole. (See MICROBIOLOGY.)
The absolute bioavailability of itraconazole administered as a non-marketed solution formulation under fed conditions was 55% in 6 healthy male volunteers. However, the bioavailability of Sporanox® (itraconazole) Oral Solution is increased under fasted conditions reaching higher maximum plasma concentrations (Cmax) in a shorter period of time. In 27 healthy male volunteers, the steady-state area under the plasma concentration versus time curve (AUC0–24h) of itraconazole (Sporanox® Oral Solution, 200 mg daily for 15 days) under fasted conditions was 131 ± 30% of that obtained under fed conditions. Therefore, unlike Sporanox® Capsules, it is recommended that Sporanox® Oral Solution be administered without food. Presented in the table below are the steady-state (Day 15) pharmacokinetic parameters for itraconazole and hydroxyitraconazole (Sporanox® Oral Solution) under fasted and fed conditions:
| Itraconazole | Hydroxyitraconazole | |||
|---|---|---|---|---|
| Fasted | Fed | Fasted | Fed | |
| ||||
| Cmax (ng/mL) | 1963 ± 601* | 1435 ± 477 | 2055 ± 487 | 1781 ± 397 |
| Tmax (hours) | 2.5 ± 0.8 | 4.4 ± 0.7 | 5.3 ± 4.3 | 4.3 ± 1.2 |
| AUC0–24h (ng∙h/mL) | 29271 ± 10285 | 22815 ± 7098 | 45184 ± 10981 | 38823 ± 8907 |
| t1/2 (hours) | 39.7 ± 13 | 37.4 ± 13 | 27.3 ± 13 | 26.1 ± 10 |
The bioavailability of Sporanox® Oral Solution relative to Sporanox® Capsules was studied in 30 healthy male volunteers who received 200 mg of itraconazole as the oral solution and capsules under fed conditions. The AUC0–∞ from Sporanox® Oral Solution was 149 ± 68% of that obtained from Sporanox® Capsules; a similar increase was observed for hydroxyitraconazole. In addition, a cross study comparison of itraconazole and hydroxyitraconazole pharmacokinetics following the administration of single 200 mg doses of Sporanox® Oral Solution (under fasted conditions) or Sporanox® Capsules (under fed conditions) indicates that when these two formulations are administered under conditions which optimize their systemic absorption, the bioavailability of the solution relative to capsules is expected to be increased further. Therefore, it is recommended that Sporanox® Oral Solution and Sporanox® Capsules not be used interchangeably. The following table contains pharmacokinetic parameters for itraconazole and hydroxyitraconazole following single 200 mg doses of Sporanox® Oral Solution (n=27) or Sporanox® Capsules (n=30) administered to healthy male volunteers under fasted and fed conditions, respectively:
| Itraconazole | Hydroxyitraconazole | |||
|---|---|---|---|---|
| Oral Solution fasted | Capsules fed | Oral Solution fasted | Capsules fed | |
| ||||
| Cmax (ng/mL) | 544 ± 213* | 302 ± 119 | 622 ± 116 | 504 ± 132 |
| Tmax (hours) | 2.2 ± 0.8 | 5 ± 0.8 | 3.5 ± 1.2 | 5 ± 1 |
| AUC0–24h (ng∙h/mL) | 4505 ± 1670 | 2682 ± 1084 | 9552 ± 1835 | 7293 ± 2144 |
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 L.
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.)
Special Populations
Pediatrics
The pharmacokinetics of Sporanox® Oral Solution were studied in 26 pediatric patients requiring systemic antifungal therapy. Patients were stratified by age: 6 months to 2 years (n=8), 2 to 5 years (n=7) and 5 to 12 years (n=11), and received itraconazole oral solution 5 mg/kg once daily for 14 days. Pharmacokinetic parameters at steady-state (Day 14) were not significantly different among the age strata and are summarized in the table below for all 26 patients:
| Itraconazole | Hydroxyitraconazole | |
|---|---|---|
| ||
| Cmax (ng/mL) | 582.5 ± 382.4* | 692.4 ± 355.0 |
| Cmin (ng/mL) | 187.5 ± 161.4 | 403.8 ± 336.1 |
| AUC0–24h (ng∙h/mL) | 7706.7 ± 5245.2 | 13356.4 ± 8942.4 |
| t1/2 (hours) | 35.8 ± 35.6 | 17.7 ± 13.0 |
Renal Insufficiency
Limited data are available on the use of oral itraconazole in patients with renal impairment. 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. × 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 AUC0–8). Plasma concentration-versus-time profiles showed wide intersubject variation in all three groups. Caution should be exercised when the drug is administered in this patient population. (See PRECAUTIONS and DOSAGE AND ADMINISTRATION.)
Hepatic Insufficiency
Itraconazole is predominantly metabolized in the liver. Patients with impaired hepatic function should be carefully monitored when taking itraconazole. A pharmacokinetic study using a single oral 100 mg capsule dose of itraconazole was conducted in 6 healthy and 12 cirrhotic subjects. 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 itraconazole, based on AUC, was similar in cirrhotic patients and in healthy subjects. The prolonged elimination half-life of itraconazole observed in the single oral dose clinical trial with itraconazole capsules in cirrhotic patients should be considered when deciding to initiate therapy with other medications metabolized by CYP3A4. Data are not available in cirrhotic patients during long-term use of itraconazole. (See BOX WARNING, 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® Oral Solution, monitor carefully and consider other treatment alternatives which may include discontinuation of Sporanox® Oral Solution administration. (See WARNINGS, PRECAUTIONS: Drug Interactions and ADVERSE REACTIONS: Post-marketing Experience for more information.)
Cystic Fibrosis
Seventeen cystic fibrosis patients, ages 7 to 28 years old, were administered itraconazole oral solution 2.5 mg/kg b.i.d. for 14 days in a pharmacokinetic study. Sixteen patients completed the study. Steady state trough concentrations >250 ng/mL were achieved in 6 out of 11 patients ≥16 years of age but in none of the 5 patients <16 years of age. Large variability was observed in the pharmacokinetic data (%CV for trough concentrations = 98% and 70% for ≥16 and <16 years, respectively; %CV for AUC = 75% and 58% for ≥16 and <16 years, respectively). If a patient with cystic fibrosis does not respond to Sporanox® Oral Solution, consideration should be given to switching to alternative therapy.
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 has been shown to be active against most strains of the following microorganisms, both in vitro and in clinical infections.
- Aspergillus flavus
- Aspergillus fumigatus
- Blastomyces dermatitidis
- Candida albicans
- Histoplasma capsulatum
- Histoplasma duboisii
(Applicable to Candida isolates from patients with oropharyngeal or esophageal candidiasis)
Candida albicans
The interpretive criteria and breakpoints for itraconazole against Candida albicans are applicable to tests performed using Clinical Laboratory and Standards Institute (CLSI) microbroth dilution reference method M27A for MIC (partial inhibition endpoint) read at 48 hours.
Broth Microdilution Techniques
Quantitative methods are used to determine antifungal minimum inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of Candida spp. to antifungal agents. MICs should be determined using a standardized procedure at 48 hours. Standardized procedures are based on a microdilution method (broth) with standardized inoculum concentrations and standardized concentrations of itraconazole powder. The MIC values should be interpreted according to the criteria provided in Table below:
| Pathogen | Broth Microdilution MIC* (µg/mL) at 48 Hours | ||
|---|---|---|---|
| S | I | R | |
| |||
| Candida albicans | ≤ 0.125 | 0.25 – 0.5 | ≥ 1 |
Standardized susceptibility test procedures require the use of quality control organisms to control the technical aspects of the test procedures. Standard itraconazole powder should provide the following range of values noted in the table below.
NOTE: Quality control microorganisms are specific strains of organisms with intrinsic biological properties relating to resistance mechanisms and their genetic expression within fungi; the specific strains used for microbiological control are not clinically significant.
| QC Strain | Broth Microdilution MIC (µg/mL) at 48 Hours |
|---|---|
| |
| Candida parapsilosis ATCC* 22019 | 0.06–0.25 |
| Candida krusei ATCC 6258 | 0.12–0.5 |
Activity in Animal Models
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 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.
Candida krusei, Candida glabrata and Candida tropicalis are generally the least susceptible Candida species, with some isolates showing unequivocal resistance to itraconazole in vitro.
Itraconazole is not active against Zygomycetes (e.g., Rhizopus spp., Rhizomucor spp., Mucor spp. and Absidia spp.), Fusarium spp., Scedosporium spp. and Scopulariopsis spp.
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.
Clinical Studies
Oropharyngeal Candidiasis
Two randomized, controlled studies for the treatment of oropharyngeal candidiasis have been conducted (total n=344). In one trial, clinical response to either 7 or 14 days of itraconazole oral solution, 200 mg/day, was similar to fluconazole tablets and averaged 84% across all arms. Clinical response in this study was defined as cured or improved (only minimal signs and symptoms with no visible lesions). Approximately 5% of subjects were lost to follow-up before any evaluations could be performed. Response to 14 days therapy of itraconazole oral solution was associated with a lower relapse rate than 7 days of itraconazole therapy. In another trial, the clinical response rate (defined as cured or improved) for itraconazole oral solution was similar to clotrimazole troches and averaged approximately 71% across both arms, with approximately 3% of subjects lost to follow-up before any evaluations could be performed. Ninety-two percent of the patients in these studies were HIV seropositive.
In an uncontrolled, open-label study of selected patients clinically unresponsive to fluconazole tablets (n=74, all patients HIV seropositive), patients were treated with itraconazole oral solution 100 mg b.i.d. (Clinically unresponsive to fluconazole in this study was defined as having received a dose of fluconazole tablets at least 200 mg/day for a minimum of 14 days.) Treatment duration was 14–28 days based on response. Approximately 55% of patients had complete resolution of oral lesions. Of patients who responded and then entered a follow-up phase (n=22), all relapsed within 1 month (median 14 days) when treatment was discontinued. Although baseline endoscopies had not been performed, several patients in this study developed symptoms of esophageal candidiasis while receiving therapy with itraconazole oral solution. Itraconazole oral solution has not been directly compared to other agents in a controlled trial of similar patients.
Esophageal Candidiasis
A double-blind randomized study (n=119, 111 of whom were HIV seropositive) compared itraconazole oral solution (100 mg/day) to fluconazole tablets (100 mg/day). The dose of each was increased to 200 mg/day for patients not responding initially. Treatment continued for 2 weeks following resolution of symptoms, for a total duration of treatment of 3–8 weeks. Clinical response (a global assessment of cured or improved) was not significantly different between the two study arms, and averaged approximately 86% with 8% lost to follow-up. Six of 53 (11%) itraconazole-treated patients and 12/57 (21%) fluconazole-treated patients were escalated to the 200 mg dose in this trial. Of the subgroup of patients who responded and entered a follow-up phase (n=88), approximately 23% relapsed across both arms within 4 weeks.
Indications and Usage for Sporanox
Sporanox® (itraconazole) Oral Solution is indicated for the treatment of oropharyngeal and esophageal candidiasis.
(See CLINICAL PHARMACOLOGY: Special Populations, WARNINGS, and ADVERSE REACTIONS: Post-marketing Experience for more information.)
Contraindications
Congestive Heart Failure
Sporanox® (itraconazole) Oral Solution should not be administered to patients with evidence of ventricular dysfunction such as congestive heart failure (CHF) or a history of CHF except for the treatment of life-threatening or other serious infections. (See CLINICAL PHARMACOLOGY: Special Populations, WARNINGS, PRECAUTIONS: Drug Interactions-Calcium Channel Blockers, and ADVERSE REACTIONS: Post-marketing Experience.)
Drug Interactions
Concomitant administration of Sporanox® (itraconazole) Capsules 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, nisoldipine, 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.)
Sporanox® is contraindicated for patients who have shown hypersensitivity to itraconazole or its excipients. There is no 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
Sporanox® (itraconazole) Oral Solution and Sporanox® Capsules should not be used interchangeably. Only Sporanox® Oral Solution has been demonstrated effective for oral and/or esophageal candidiasis. Sporanox® Oral Solution contains the excipient hydroxypropyl-β-cyclodextrin which produced pancreatic adenocarcinomas in a rat carcinogenicity study. These findings were not observed in a similar mouse carcinogenicity study. The clinical relevance of these findings is unknown. (See Carcinogenesis, Mutagenesis, and Impairment of Fertility.)
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 cisapride, pimozide, levacetylmethadol (levomethadyl), or quinidine concomitantly with Sporanox® and/or other CYP3A4 inhibitors. Concomitant administration of these drugs with Sporanox® is contraindicated. (See BOX WARNING, CONTRAINDICATIONS, and PRECAUTIONS: Drug Interactions.)
Cardiac Disease
Sporanox® Oral Solution should not be used 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® Oral Solution, monitor carefully and consider other treatment alternatives which may include discontinuation of Sporanox® Oral Solution 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 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, PRECAUTIONS: Drug Interactions, and ADVERSE REACTIONS: Post-marketing Experience for more information.)
Cystic Fibrosis
If a patient with cystic fibrosis does not respond to Sporanox® Oral Solution, consideration should be given to switching to alternative therapy (see CLINICAL PHARMACOLOGY: Special Populations).
Treatment of Severely Neutropenic Patients
Sporanox® Oral Solution as treatment for oropharyngeal and/or esophageal candidiasis was not investigated in severely neutropenic patients. Due to its pharmacokinetic properties, Sporanox® Oral Solution is not recommended for initiation of treatment in patients at immediate risk of systemic candidiasis.
Precautions
Hepatotoxicity
Rare cases of serious hepatotoxicity have been observed with Sporanox® treatment, including some cases within the first week. 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. Liver function monitoring should be done in patients with pre-existing hepatic function abnormalities or those who have experienced liver toxicity with other medications and should 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® Oral Solution, the treatment should be discontinued.
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 BOX 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
- Only Sporanox® Oral Solution has been demonstrated effective for oral and/or esophageal candidiasis. Sporanox® Oral Solution contains the excipient hydroxypropyl-β-cyclodextrin which produced pancreatic adenocarcinomas in a rat carcinogenicity study. These findings were not observed in a similar mouse carcinogenicity study. The clinical relevance of these findings is unknown. (See Carcinogenesis, Mutagenesis, and Impairment of Fertility.)
- Taking Sporanox® Oral Solution under fasted conditions improves the systemic availability of itraconazole. Instruct patients to take Sporanox® Oral Solution without food, if possible.
- Sporanox® Oral Solution should not be used interchangeably with Sporanox® Capsules.
- 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.
Drug Interactions
Itraconazole and its major metabolite, hydroxyitraconazole, are inhibitors of CYP3A4. Therefore, the following drug interactions may occur (See Table 1 below and the drug class subheadings that follow):
- Sporanox® may decrease the elimination of drugs metabolized by CYP3A4, resulting in increased plasma concentrations of these drugs when they are administered with Sporanox®. These elevated plasma concentrations may increase or prolong both therapeutic and adverse effects of these drugs. Whenever possible, plasma concentrations of these drugs should be monitored, and dosage adjustments made after concomitant Sporanox® therapy is initiated. When appropriate, clinical monitoring for signs or symptoms of increased or prolonged pharmacologic effects is advised. Upon discontinuation, depending on the dose and duration of treatment, itraconazole plasma concentrations decline gradually (especially in patients with hepatic cirrhosis or in those receiving CYP3A4 inhibitors). This is particularly important when initiating therapy with drugs whose metabolism is affected by itraconazole.
- Inducers of CYP3A4 may decrease the plasma concentrations of itraconazole. Sporanox® may not be effective in patients concomitantly taking Sporanox® and one of these drugs. Therefore, administration of these drugs with Sporanox® is not recommended.
- Other inhibitors of CYP3A4 may increase the plasma concentrations of itraconazole. Patients who must take Sporanox® concomitantly with one of these drugs should be monitored closely for signs or symptoms of increased or prolonged pharmacologic effects of Sporanox®.
| Drug plasma concentration increased by itraconazole | |
|---|---|
| |
| Antiarrhythmics | digoxin, dofetilide,† quinidine,† disopyramide |
| Anticoagulants | warfarin |
| Anticonvulsants | carbamazepine |
| Antimycobacterials | rifabutin |
| Antineoplastics | busulfan, docetaxel, vinca alkaloids |
| Antipsychotics | pimozide† |
| Benzodiazepines | alprazolam, diazepam, midazolam,†, ‡ triazolam† |
| Calcium Channel Blockers | dihydropyridines (including nisoldipine†), verapamil |
| Gastrointestinal Motility Agents | cisapride† |
| HMG CoA-Reductase Inhibitors | atorvastatin, cerivastatin, lovastatin,† simvastatin† |
| Immunosuppressants | cyclosporine, tacrolimus, sirolimus |
| Oral Hypoglycemics | oral hypoglycemics |
| Protease Inhibitors | indinavir, ritonavir, saquinavir |
| Other | levacetylmethadol (levomethadyl),† ergot alkaloids,† halofantrine, alfentanil, buspirone, methylprednisolone, budesonide, dexamethasone, fluticasone, trimetrexate, warfarin, cilostazol, eletriptan, fentanyl |
| Decrease plasma concentration of itraconazole | |
| Anticonvulsants | carbamazepine, phenobarbital, phenytoin |
| Antimycobacterials | isoniazid, rifabutin, rifampin |
| Gastric Acid Suppressors/Neutralizers | antacids, H2-receptor antagonists, proton pump inhibitors |
| Reverse Transcriptase Inhibitors | nevirapine |
| Increase plasma concentration of itraconazole | |
| Macrolide Antibiotics | clarithromycin, erythromycin |
| Protease Inhibitors | indinavir, ritonavir |
Antiarrhythmics
The class IA antiarrhythmic quinidine and class III antiarrhythmic dofetilide are known to prolong the QT interval. Coadministration of quinidine or dofetilide with Sporanox® may increase plasma concentrations of quinidine or dofetilide which could result in serious cardiovascular events. Therefore, concomitant administration of Sporanox® and quinidine or dofetilide is contraindicated. (See BOX WARNING, CONTRAINDICATIONS, and WARNINGS.)
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.
Concomitant administration of digoxin and Sporanox® has led to increased plasma concentrations of digoxin via inhibition of P-glycoprotein.
Anticoagulants
Sporanox® enhances the anticoagulant effect of coumarin-like drugs, such as warfarin.
Anticonvulsants
Reduced plasma concentrations of itraconazole were reported when Sporanox® was administered concomitantly with phenytoin. Carbamazepine, phenobarbital, and phenytoin are all inducers of CYP3A4. Although interactions with carbamazepine and phenobarbital have not been studied, concomitant administration of Sporanox® and these drugs would be expected to result in decreased plasma concentrations of itraconazole. In addition, in vivo studies have demonstrated an increase in plasma carbamazepine concentrations in subjects concomitantly receiving ketoconazole. Although there are no data regarding the effect of itraconazole on carbamazepine metabolism, because of the similarities between ketoconazole and itraconazole, concomitant administration of Sporanox® and carbamazepine may inhibit the metabolism of carbamazepine.
Antimycobacterials
Drug interaction studies have demonstrated that plasma concentrations of azole antifungal agents and their metabolites, including itraconazole and hydroxyitraconazole, were significantly decreased when these agents were given concomitantly with rifabutin or rifampin. In vivo data suggest that rifabutin is metabolized in part by CYP3A4. Sporanox® may inhibit the metabolism of rifabutin. Although no formal study data are available for isoniazid, similar effects should be anticipated. Therefore, the efficacy of Sporanox® could be substantially reduced if given concomitantly with one of these agents. Coadministration is not recommended.
Antineoplastics
Sporanox® may inhibit the metabolism of busulfan, docetaxel, and vinca alkaloids.
Antipsychotics
Pimozide is known to prolong the QT interval and is partially metabolized by CYP3A4. Coadministration of pimozide with Sporanox® could result in serious cardiovascular events. Therefore, concomitant administration of Sporanox® and pimozide is contraindicated. (See BOX WARNING, CONTRAINDICATIONS, and WARNINGS.)
Benzodiazepines
Concomitant administration of Sporanox® and alprazolam, diazepam, oral midazolam, or triazolam could lead to increased plasma concentrations of these benzodiazepines. Increased plasma concentrations could potentiate and prolong hypnotic and sedative effects. Concomitant administration of Sporanox® and oral midazolam or triazolam is contraindicated. (See CONTRAINDICATIONS and WARNINGS.) If midazolam is administered parenterally, special precaution and patient monitoring are required since the sedative effect may be prolonged.
Calcium Channel Blockers
Edema has been reported in patients concomitantly receiving Sporanox® and dihydropyridine calcium channel blockers. Appropriate dosage adjustment may be necessary.
Calcium channel blockers can have a negative inotropic effect which may be additive to those of itraconazole; itraconazole can inhibit the metabolism of calcium channel blockers such as dihydropyridines (e.g., nifedipine and felodipine) and verapamil. 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 nisoldipine results in clinically significant increases in nisoldipine plasma concentrations, which cannot be managed by dosage reduction. Therefore the concomitant administration of Sporanox® and nisoldipine is contraindicated. (See CLINICAL PHARMACOLOGY: Special Populations, CONTRAINDICATIONS, WARNINGS, and ADVERSE REACTIONS: Post-marketing Experience for more information.)
Gastric Acid Suppressors/Neutralizers
Reduced plasma concentrations of itraconazole were reported when Sporanox® C
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