Sporanox Information
Sporanox (Itraconazole)
Sporanox (Itraconazole) Description
Sporanox (Itraconazole) 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-[(*)--butyl]-4-[-[4-[-[[(2*,4*)-2-(2,4-dichlorophenyl)-2-(1-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1-piperazinyl]phenyl]-Δ-1,2,4-triazolin-5-one mixture with (±)-1-[(*)--butyl]-4-[-[4-[-[[(2*,4*)-2-(2,4-dichlorophenyl)-2-(1-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1-piperazinyl]phenyl]-Δ-1,2,4-triazolin-5-one
or
(±)-1-[()--butyl]-4-[-[4-[-[[(2,4)-2-(2,4-dichlorophenyl)-2-(1-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1-piperazinyl]phenyl]-Δ-1,2,4-triazolin-5-one.
Itraconazole has a molecular formula of CHClNO 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 (Itraconazole) 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 (Itraconazole) Clinical Pharmacology
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.)
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 (C) in a shorter period of time. In 27 healthy male volunteers, the steady-state area under the plasma concentration versus time curve (AUC) of itraconazole (Sporanox (Itraconazole) Oral Solution, 200 mg daily for 15 days) under fasted conditions was 131 ± 30% of that obtained under fed conditions. Therefore, unlike Sporanox (Itraconazole) Capsules, it is recommended that Sporanox (Itraconazole) Oral Solution be administered without food. Presented in the table below are the steady-state (Day 15) pharmacokinetic parameters for itraconazole and hydroxyitraconazole (Sporanox (Itraconazole) Oral Solution) under fasted and fed conditions:
The bioavailability of Sporanox (Itraconazole) Oral Solution relative to Sporanox (Itraconazole) Capsules was studied in 30 healthy male volunteers who received 200 mg of itraconazole as the oral solution and capsules under fed conditions. The AUC from Sporanox (Itraconazole) Oral Solution was 149 ± 68% of that obtained from Sporanox (Itraconazole) 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 (Itraconazole) Oral Solution (under fasted conditions) or Sporanox (Itraconazole) 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 (Itraconazole) Oral Solution and Sporanox (Itraconazole) Capsules not be used interchangeably. The following table contains pharmacokinetic parameters for itraconazole and hydroxyitraconazole following single 200 mg doses of Sporanox (Itraconazole) Oral Solution (n=27) or Sporanox (Itraconazole) Capsules (n=30) administered to healthy male volunteers under fasted and fed conditions, respectively:
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. (Seeandfor more information.)
Sporanox (Itraconazole) Microbiology
In vitro
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 and
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 disseminatedinfections. 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 pulmonaryinfection, respectively. Itraconazole has demonstrated antifungal activity in a variety of animal models infected withand otherspecies.
Isolates from several fungal species with decreased susceptibility to itraconazole have been isolatedand from patients receiving prolonged therapy.
Severalstudies have reported that some fungal clinical isolates, includingspecies, 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 thesesusceptibility data to clinical outcome remains to be elucidated.
Itraconazole is not active against(e.g.,spp.,spp.,spp. andspp.),spp.,spp. andspp.
Studies (bothand) suggest that the activity of amphotericin B may be suppressed by prior azole antifungal therapy. As with other azoles, itraconazole inhibits the C-demethylation step in the synthesis of ergosterol, a cell wall component of fungi. Ergosterol is the active site for amphotericin B. In one study the antifungal activity of amphotericin B againstinfections in mice was inhibited by ketoconazole therapy. The clinical significance of test results obtained in this study is unknown.
Sporanox (Itraconazole) Clinical Studies
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.
Sporanox (Itraconazole) Indications And Usage
Sporanox (Itraconazole) Oral Solution is indicated for the treatment of oropharyngeal and esophageal candidiasis.
(See,, andfor more information.)
Sporanox (Itraconazole) Contraindications
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 (Itraconazole) . HMG CoA-reductase inhibitors metabolized by CYP3A4, such as lovastatin and simvastatin, are also contraindicated with Sporanox (Itraconazole) . Ergot alkaloids metabolized by CYP3A4 such as dihydroergotamine, ergometrine (ergonovine), ergotamine and methylergometrine (methylergonovine) are contraindicated with Sporanox (Itraconazole) . (See, and.)
Sporanox (Itraconazole) 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 (Itraconazole) to patients with hypersensitivity to other azoles.
Sporanox (Itraconazole) Warnings
Sporanox (Itraconazole) Oral Solution and Sporanox (Itraconazole) Capsules should not be used interchangeably. Only Sporanox (Itraconazole) Oral Solution has been demonstrated effective for oral and/or esophageal candidiasis. Sporanox (Itraconazole) 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.)
Sporanox (Itraconazole) 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 (Itraconazole) use or reinstitution of treatment with Sporanox (Itraconazole) is strongly discouraged unless there is a serious or life-threatening situation where the expected benefit exceeds the risk.
Sporanox (Itraconazole) 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 (Itraconazole) therapy. These risk factors include cardiac disease such as ischemic and valvular disease; significant pulmonary disease such as chronic obstructive pulmonary disease; and renal failure and other edematous disorders. Such patients should be informed of the signs and symptoms of CHF, should be treated with caution, and should be monitored for signs and symptoms of CHF during treatment. If signs or symptoms of CHF appear during administration of Sporanox (Itraconazole) Oral Solution, monitor carefully and consider other treatment alternatives which may include discontinuation of Sporanox (Itraconazole) 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 (Itraconazole) 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 (Itraconazole) 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,, andfor more information.)
Sporanox (Itraconazole) Precautions
Itraconazole showed no evidence of carcinogenicity potential in mice treated orally for 23 months at dosage levels up to 80 mg/kg/day (approximately 10x the maximum recommended human dose [MRHD]). Male rats treated with 25 mg/kg/day (3.1x MRHD) had a slightly increased incidence of soft tissue sarcoma. These sarcomas may have been a consequence of hypercholesterolemia, which is a response of rats, but not dogs or humans, to chronic itraconazole administration. Female rats treated with 50 mg/kg/day (6.25x MRHD) had an increased incidence of squamous cell carcinoma of the lung (2/50) as compared to the untreated group. Although the occurrence of squamous cell carcinoma in the lung is extremely uncommon in untreated rats, the increase in this study was not statistically significant.
Hydroxypropyl-β-cyclodextrin (HP-β-CD), the solubilizing excipient used in Sporanox (Itraconazole) Oral Solution, was found to produce pancreatic exocrine hyperplasia and neoplasia when administered orally to rats at doses of 500, 2000 or 5000 mg/kg/day for 25 months. Adenocarcinomas of the exocrine pancreas produced in the treated animals were not seen in the untreated group and are not reported in the historical controls. Development of these tumors may be related to a mitogenic action of cholecystokinin. This finding was not observed in the mouse carcinogenicity study at doses of 500, 2000 or 5000 mg/kg/day for 22–23 months; however, the clinical relevance of these findings is unknown. Based on body surface area comparisons, the exposure to humans of HP-β-CD at the recommended clinical dose of Sporanox (Itraconazole) Oral Solution is approximately equivalent to 1.7 times the exposure at the lowest dose in the rat study.
Itraconazole produced no mutagenic effects when assayed in a DNA repair test (unscheduled DNA synthesis) in primary rat hepatocytes, in Ames tests with(6 strains) and, in the mouse lymphoma gene mutation tests, in a sex-linked recessive lethal mutation () test, in chromosome aberration tests in human lymphocytes, in a cell transformation test with C3H/10T½ C18 mouse embryo fibroblasts cells, in a dominant lethal mutation test in male and female mice, and in micronucleus tests in mice and rats.
Itraconazole did not affect the fertility of male or female rats treated orally with dosage levels of up to 40 mg/kg/day (5x MRHD), even though parental toxicity was present at this dosage level. More severe signs of parental toxicity, including death, were present in the next higher dosage level, 160 mg/kg/day (20x MRHD).
The efficacy and safety of Sporanox (Itraconazole) have not been established in pediatric patients. A pharmacokinetic study was conducted with Sporanox (Itraconazole) Oral Solution in 26 pediatric patients, ages 6 months to 12 years, requiring systemic antifungal treatment. Itraconazole was dosed at 5 mg/kg once daily for two weeks and no serious unexpected adverse events were reported. (See.)
The long-term effects of itraconazole on bone growth in children are unknown. In three toxicology studies using rats, itraconazole induced bone defects at dosage levels as low as 20 mg/kg/day (2.5x MRHD). The induced defects included reduced bone plate activity, thinning of the zona compacta of the large bones, and increased bone fragility. At a dosage level of 80 mg/kg/day (10x MRHD) over 1 year or 160 mg/kg/day (20x MRHD) for 6 months, itraconazole induced small tooth pulp with hypocellular appearance in some rats. No such bone toxicity has been reported in adult patients.
Sporanox (Itraconazole) Adverse Reactions
Sporanox (Itraconazole) has been associated with rare cases of serious hepatotoxicity, including liver failure and death. Some of these cases had neither pre-existing liver disease nor a serious underlying medical condition. If clinical signs or symptoms develop that are consistent with liver disease, treatment should be discontinued and liver function testing performed. The risks and benefits of Sporanox (Itraconazole) use should be reassessed. (Seeandand.)
U.S. adverse experience data are derived from 350 immunocompromised patients (332 HIV seropositive/AIDS) treated for oropharyngeal or esophageal candidiasis. below lists adverse events reported by at least 2% of patients treated with Sporanox (Itraconazole) Oral Solution in U.S. clinical trials. Data on patients receiving comparator agents in these trials are included for comparison.
Adverse events reported by less than 2% of patients in U.S. clinical trials with Sporanox (Itraconazole) included: adrenal insufficiency, asthenia, back pain, dehydration, dyspepsia, dysphagia, flatulence, gynecomastia, hematuria, hemorrhoids, hot flushes, implantation complication, infection unspecified, injury, insomnia, male breast pain, myalgia, pharyngitis, pruritus, rhinitis, rigors, stomatitis ulcerative, taste perversion, tinnitus, upper respiratory tract infection, vision abnormal, and weight decrease. Edema, hypokalemia and menstrual disorders have been reported in clinical trials with itraconazole capsules.
Adverse drug reactions that have been identified during post-approval use of Sporanox (Itraconazole) (all formulations) are listed in the table below. Because these reactions are reported voluntarily from a population of uncertain size, reliably estimating their frequency or establishing a causal relationship to drug exposure is not always possible.
There is limited information on the use of Sporanox (Itraconazole) during pregnancy. Cases of congenital abnormalities including skeletal, genitourinary tract, cardiovascular and ophthalmic malformations as well as chromosomal and multiple malformations have been reported during post-marketing experience. A causal relationship with Sporanox (Itraconazole) has not been established. (See,,, andfor more information.)
Sporanox (Itraconazole) Overdosage
Itraconazole is not removed by dialysis. In the event of accidental overdosage, supportive measures, including gastric lavage with sodium bicarbonate, should be employed.
There are limited data on the outcomes of patients ingesting high doses of itraconazole. In patients taking either 1000 mg of Sporanox (Itraconazole) Oral Solution or up to 3000 mg of Sporanox (Itraconazole) Capsules, the adverse event profile was similar to that observed at recommended doses.
Sporanox (Itraconazole) Dosage And Administration
The solution should be vigorously swished in the mouth (10 mL at a time) for several seconds and swallowed.
The recommended dosage of Sporanox (Itraconazole) Oral Solution for oropharyngeal candidiasis is 200 mg (20 mL) daily for 1 to 2 weeks. Clinical signs and symptoms of oropharyngeal candidiasis generally resolve within several days.
For patients with oropharyngeal candidiasis unresponsive/refractory to treatment with fluconazole tablets, the recommended dose is 100 mg (10 mL) b.i.d. For patients responding to therapy, clinical response will be seen in 2 to 4 weeks. Patients may be expected to relapse shortly after discontinuing therapy. Limited data on the safety of long-term use (>6 months) of Sporanox (Itraconazole) Oral Solution are available at this time.
The recommended dosage of Sporanox (Itraconazole) Oral Solution for esophageal candidiasis is 100 mg (10 mL) daily for a minimum treatment of three weeks. Treatment should continue for 2 weeks following resolution of symptoms. Doses up to 200 mg (20 mL) per day may be used based on medical judgment of the patient's response to therapy.
Sporanox (Itraconazole) Oral Solution and Sporanox (Itraconazole) Capsules should not be used interchangeably. Patients should be instructed to take Sporanox (Itraconazole) Oral Solution without food, if possible. Only Sporanox (Itraconazole) Oral Solution has been demonstrated effective for oral and/or esophageal candidiasis.
Use in Patients with Renal Impairment
Limited data are available on the use of oral itraconazole in patients with renal impairment. Caution should be exercised when this drug is administered in this patient population. (Seeand.)
Use in Patients with Hepatic Impairment
Limited data are available on the use of oral itraconazole in patients with hepatic impairment. Caution should be exercised when this drug is administered in this patient population. (Seeand.)
Sporanox (Itraconazole) How Supplied
Sporanox (Itraconazole) Oral Solution is available in 150 mL amber glass bottles (NDC 50458-295-15) containing 10 mg of itraconazole per mL.
Sporanox (Itraconazole)
Sporanox (Itraconazole) Principal Display Panel - Ml Bottle
Store bottle at or below25°C (77°F). Do not freeze.
978848 Revised 08/2010
Manufactured by: Janssen Pharmaceutica N.V. Beerse, Belgium
Manufactured for:Centocor Ortho Biotech Products, L.P.Raritan, NJ 08869
