Sporanox

Itraconazole.

Capsule: Each capsule, for oral administration, contains 100 mg itraconazole in a pellet formulation, and is available as a blue opaque cap and pink transparent body.
Oral solution: 1 mL SPORANOX Oral Solution contains 10 mg itraconazole.
Excipients/Inactive Ingredients: Capsule: The inactive ingredients of the capsules are hypromellose, macrogol, and sugar spheres (composed of maize starch, purified water, and sucrose).
The capsule itself contains erythrosine sodium, gelatin, indogitin disulfonate sodium, titanium dioxide.
Oral solution: Caramel, cherry flavor 1, cherry flavor 2, hydrochloric acid, hydroxypropyl-β-cyclodextrin, propylene glycol, purified water, sodium hydroxide, sodium saccharin, sorbitol.

Pharmacotherapeutic Group: Antimycotic for systemic use, triazole and tetrazole derivatives. ATC Code: J02A C02.
Pharmacology: Pharmacodynamics: Mechanism of action: In vitro studies have demonstrated that itraconazole impairs the synthesis of ergosterol in fungal cells. Ergosterol is a vital cell membrane component in fungi. Impairment of its synthesis ultimately results in an antifungal effect.
Pharmacokinetic (PK)/Pharmacodynamic (PD) relationship: The PK/PD relationship for itraconazole, and for triazoles in general, is poorly understood.
Pharmacodynamic effects: Microbiology: Itraconazole, a triazole derivative, has a broad spectrum of activity.
For itraconazole, interpretive breakpoints have not been established by CLSI for the Candida spp. and the filamentous fungi.
EUCAST breakpoints or itraconazole have been established for Aspergillus flavus, A. fumigatus, A. nidulans and A. terreus, and are as follows: susceptible ≤1 mg/L, resistant >1 mg/L. EUCAST breakpoints for itraconazole have been established for Candida albicans and C. dubliniensis, and are as follows: susceptible ≤0.06 mg/L, resistant >0.06 mg/L. EUCAST breakpoints for itraconazole have been established for Candida parapsilosis and C. tropicalis, and are as follows: susceptible ≤0.125 mg/L, resistant >0.125 mg/L. Interpretive breakpoints have not been established by EUCAST for Candida glabrata, C. krusei, C. guilliermondii, Cryptococcus neoformans, Aspergillus niger, and Non-species related breakpoints for Candida and Aspergillus.
In vitro studies demonstrate that itraconazole inhibits the growth of a broad range of fungi pathogenic for humans at concentrations usually ≤1 μg/mL. These include: Aspergillus spp., Blastomyces dermatitidis, Cladosporium spp., Coccidioides immitis, Cryptococcus neoformans, Geotrichum spp., Histoplasma spp., including H. capsulatum, Paracoccidioides brasiliensis, Penicillium marneffei, Sporothrix schenckii and Trichosporon spp. Itraconazole also displayed activity in vitro against Epidermophyton floccosum, Fonsecaea spp., Malassezia spp., Microsporum spp., Pseudallescheria boydii, Trichophyton spp. and various other yeasts and fungi.
The principal fungus types that are not inhibited by itraconazole are Zygomycetes (e.g., Rhizopus spp., Rhizomucor spp., Mucor spp. and Absidia spp.), Fusarium spp., Scedosporium spp. and Scopulariopsis spp.
Azole resistance appears to develop slowly and is often the result of several genetic mutations. Mechanisms that have been described are overexpression of ERG11, which encodes the target enzyme 14α-demethylase, point mutations in ERG11 that lead to decreased target affinity and/or transporter overexpression resulting in increased efflux. Cross-resistance between members of the azole class has been observed within Candida spp., although resistance to one member of the class does not necessarily confer resistance to other azoles. Itraconazole-resistant strains of Aspergillus fumigatus have been reported.
Pharmacokinetics: General pharmacokinetic characteristics: Peak plasma concentrations of itraconazole are reached within 2 to 5 hours following oral administration. As a consequence of non-linear pharmacokinetics, itraconazole accumulates in plasma during multiple dosing. Steady-state concentrations are generally reached within about 15 days, with C_max values of 0.5 μg/mL, 1.1 μg/mL and 2.0 μg/mL after oral administration of 100 mg once daily, 200 mg once daily and 200 mg b.i.d., respectively. The terminal half-life of itraconazole generally ranges from 16 to 28 hours after single dose and increases to 34 to 42 hours with repeated dosing. Once treatment is stopped, itraconazole plasma concentrations decrease to an almost undetectable concentration within 7 to 14 days, depending on the dose and duration of treatment. Itraconazole mean total plasma clearance following intravenous administration is 278 mL/min. Itraconazole clearance decreases at higher doses due to saturable hepatic metabolism.
Absorption: Capsule: Itraconazole is rapidly absorbed after oral administration. Peak plasma concentrations of the unchanged drug are reached within 2 to 5 hours following an oral capsule dose. The observed absolute oral bioavailability of itraconazole is about 55%. Oral bioavailability is maximal when the capsules are taken immediately after a full meal.
Absorption of itraconazole capsules is reduced in subjects with reduced gastric acidity, such as subjects taking medications known as gastric acid secretion suppressors (e.g., H₂-receptor antagonists, proton pump inhibitors) or subjects with achlorhydria caused by certain diseases (see Precautions, and Interactions). Absorption of itraconazole under fasted conditions in these subjects is increased when SPORANOX capsules are administered with an acidic beverage (such as a non-diet cola). When SPORANOX capsules were administered as a single 200-mg dose under fasted conditions with non-diet cola after ranitidine pretreatment, a H₂-receptor antagonist, itraconazole absorption was comparable to that observed when SPORANOX capsules were administered alone. (See Interactions.)
Itraconazole exposure is lower with the capsule formulation than with the oral solution when the same dose of drug is given. (See Precautions.)
Oral solution: Itraconazole is rapidly absorbed after administration of the oral solution. Peak plasma concentrations of itraconazole are reached within 2.5 hours following administration of the oral 30 solution under fasting conditions. The observed absolute bioavailability of itraconazole under fed conditions is about 55% and increases by 30% when the oral solution is taken in fasting conditions.
Itraconazole exposure is greater with the oral solution than with the capsule formulation when the same dose of drug is given. (See Precautions.)
Distribution: Most of the itraconazole in plasma is bound to protein (99.8%) with albumin being the main binding component (99.6% for the hydroxy-metabolite). It has also a marked affinity for lipids. Only 0.2% of the itraconazole in plasma is present as free drug. Itraconazole is distributed in a large apparent volume in the body (> 700 L), suggesting extensive distribution into tissues. Concentrations in lung, kidney, liver, bone, stomach, spleen and muscle were found to be two to three times higher than corresponding concentrations in plasma, and the uptake into keratinous tissues, skin in particular, up to four times higher. Concentrations in the cerebrospinal fluid are much lower than in plasma, but efficacy has been demonstrated against infections present in the cerebrospinal fluid.
Metabolism: Itraconazole is extensively metabolized by the liver into a large number of metabolites. In vitro studies have shown that CYP3A4 is the major enzyme involved in the metabolism of itraconazole. The main metabolite is hydroxy-itraconazole, which has in vitro antifungal activity comparable to itraconazole; trough plasma concentrations of this metabolite are about twice those of itraconazole.
Excretion: Itraconazole is excreted mainly as inactive metabolites in urine (35%) and in feces (54%) within one week of an oral solution dose. Renal excretion of itraconazole and the active metabolite hydroxy-itraconazole account for less than 1% of an intravenous dose. Based on an oral radiolabeled dose, fecal excretion of unchanged drug ranges from 3% to 18% of the dose.
As re-distribution of itraconazole from keratinous tissues appears to be negligible, elimination of itraconazole from these tissues is related to epidermal regeneration. Contrary to plasma, the concentration in skin persists for 2 to 4 weeks after discontinuation of a 4-week treatment and in nail keratin - where itraconazole can be detected as early as 1 week after start of treatment - for at least six months after the end of a 3-month treatment period.
Special populations: Hepatic impairment: Itraconazole is predominantly metabolized in the liver. A pharmacokinetic study was conducted in 6 healthy and 12 cirrhotic subjects who were administered a single 100-mg dose of itraconazole as a capsule. A statistically significant reduction in mean C_max (47%) and a twofold increase in the elimination half-life (37 ± 17 hours vs. 16 ± 5 hours) of itraconazole were noted in cirrhotic subjects compared with healthy subjects. However, overall exposure to itraconazole, based on AUC, was similar in cirrhotic patients and in healthy subjects. Data are not available in cirrhotic patients during long-term use of itraconazole. (See Dosage & Administration, and Precautions).
Renal impairment: Limited data are available on the use of oral itraconazole in patients with renal impairment. A pharmacokinetic study using a single 200-mg 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 (T_max, C_max, and AUC_0-8h). Plasma concentration-versus-time profiles showed wide intersubject variation in all three groups.
After a single intravenous dose, the mean terminal half-lives of itraconazole in patients with mild (defined in this study as CrCl 50-79 mL/min), moderate (defined in this study as CrCl 20-49 mL/min), and severe renal impairment (defined in this study as CrCl <20 mL/min) were similar to that in healthy subjects, (range of means 42-49 hours vs 48 hours in renally impaired patients and healthy subjects, respectively.) Overall exposure to itraconazole, based on AUC, was decreased in patients with moderate and severe renal impairment by approximately 30% and 40%, respectively, as compared with subjects with normal renal function.
Data are not available renally impaired patients during long-term use of itraconazole. Dialysis has no effect on the half-life or clearance of itraconazole or hydroxy-itraconazole. (See also Dosage & Administration and Precautions.)
Pediatrics: Limited pharmacokinetic data are available on the use of itraconazole in the pediatric population. Clinical pharmacokinetic studies in children and adolescents aged between 5 months and 17 years were performed with itraconazole capsules, oral solution or intravenous formulation. Individual doses with the capsule and oral solution formulation ranged from 1.5 to 12.5 mg/kg/day, given as once-daily or twice-daily administration. The intravenous formulation was given either as a 2.5 mg/kg single infusion, or a 2.5 mg/kg infusion given once daily or twice daily. For the same daily dose, twice daily dosing compared to single daily dosing yielded peak and trough concentrations comparable to adult single daily dosing. No significant age dependence was observed for itraconazole AUC and total body clearance, while weak associations between age and itraconazole distribution volume, C_max and terminal elimination rate were noted. Itraconazole apparent clearance and distribution volume seemed to be related to weight.
Oral solution: Hydroxypropyl-β-Cyclodextrin: The oral bioavailability of hydroxypropyl-β-cyclodextrin given as a solubilizer of itraconazole in oral solution is on average lower than 0.5% and is similar to that of hydroxypropyl-β-cyclodextrin alone. This low oral bioavailability of hydroxypropyl-β-cyclodextrin is not modified by the presence of food and is similar after single and repeated administrations.
Toxicology: Non-Clinical Information: Itraconazole has been tested in a standard battery of non-clinical safety studies.
Acute oral toxicity studies with itraconazole in mice, rats, guinea pigs and dogs indicate a wide safety margin (8- to 38-fold of Maximum Recommended Human Dose [MRHD] based on mg/m²). Sub (chronic) oral toxicity studies in rats and dogs revealed several target organs or tissues: adrenal cortex, liver and mononuclear phagocyte system as well as disorders of the lipid metabolism presenting as xanthoma cells in various organs.
At high doses of 40 and 80 mg/kg/day in rats (2-and 4-fold of MRHD based on mg/m²), histological investigations of adrenal cortex showed a reversible swelling with cellular hypertrophy of the zona reticularis and fasciculata, which was sometimes associated with a thinning of the zona glomerulosa. Reversible hepatic changes were found at 40 and 160 mg/kg/day. Slight changes were observed in the sinusoidal cells and vacuolation of the hepatocytes, the latter indicating cellular dysfunction, but without visible hepatitis or hepatocellular necrosis. Histological changes of the mononuclear phagocyte system were mainly characterized by macrophages with increased proteinaceous material in various parenchymal tissues.
A global lower bone mineral density was observed in juvenile dogs after chronic itraconazole administration. No toxicity was observed up to 20 mg/kg (4-fold of MRHD based on mg/m²).
In three toxicology studies using rats, itraconazole induced bone defects. The induced defects included reduced bone plate activity, thinning of the zona compacta of the large bones, and increased bone fragility.
Carcinogenicity and mutagenicity: Itraconazole is not a primary carcinogen in rats or mice up to 20 and 80 mg/kg, respectively. In male rats, however, there was a higher incidence of soft-tissue sarcoma, which is attributed to the increase in non-neoplastic, chronic inflammatory reactions of the connective tissue as a consequence of raised cholesterol levels and cholesterosis in connective tissue.
There are no indications of a mutagenic potential of itraconazole.
Reproductive toxicology: Itraconazole was found to cause a dose-related increase in maternal toxicity, embryotoxicity, and teratogenicity in rats and mice at high doses. In rats, the teratogenicity consisted of major skeletal defects; in mice, it consisted of encephaloceles and macroglossia. The observed skeletal malformation in rats may due to maternal toxicity. No teratogenic effects were found in rabbits up to 80 mg/kg dose (9-fold of MRHD based on mg/m²).
Fertility: There is no evidence of a primary influence on fertility under treatment with itraconazole.
Oral solution: Hydroxypropyl-β-cyclodextrin (HP-β-CD): Single and repeated dose toxicity studies in mice, rats and dogs indicate a wide safety margin after oral and intravenous administration of HP-β-CD. Most effects were adaptive in nature (histological changes in the urinary tract, softening of feces related to the osmotic water retention in the large intestine, activation of the mononuclear phagocyte system) and showed good reversibility.
Slight liver changes occurred at doses of about 30 times the proposed human dose of HP-β-CD.
Oral treatment of juvenile Beagle dogs with HP-β-CD at 1200 mg/kg for a period of up to 13 weeks with a 4-week recovery period was clinically well tolerated with no effects noted when compared to control animals at laboratory or histopathology examination.
Carcinogenicity and mutagenicity: No primary carcinogenicity activity was evidenced in the mouse carcinogenicity study. In the rat carcinogenicity study, an increased incidence of neoplasms in the large intestine (at 5000 mg/kg/day) and in the exocrine pancreas (from 500 mg/kg/day) were seen. Based on a human equivalent dose calculation normalized for body surface area, the recommended clinical dose of SPORANOX Oral Solution contains approximately 1.7 times the amount of HP-β-CD as was in the 500 mg/kg/day dose administered in rats in this carcinogenicity study.
The slightly higher incidence of adenocarcinomas in the large intestines was linked to the hypertrophic/hyperplastic and inflammatory changes in the colonic mucosa brought about by HP-β-CD-induced increased osmotic forces and is considered to be of low clinical relevance. Development of the pancreatic tumors is related to the mitogenic action of cholecystokinin in rats. This finding was not observed in the mouse carcinogenicity study, nor in a 12 month toxicity study in dogs or in a 2-year toxicity study in female cynomolgus monkeys. There is no evidence that cholecystokinin has a mitogenic action in man. However, the clinical relevance of these findings is not applicable.
HP-β-CD is not mutagenic. The chemical structure of HP-β-CD does not raise suspicion for genotoxic activity. Tests on DNA-damage, gene mutations and chromosome aberrations in vitro and in vivo did not reveal any genotoxic activity.
Reproductive toxicology: HP-β-CD has no direct embryotoxic and no teratogenic effects.
Fertility: HP-β-CD has no antifertile effect.

SPORANOX capsules are indicated for the following conditions: Gynecological indications: Treatment of vulvovaginal candidosis.
Dermatological/mucosal/ophthalmological indications: Treatment of dermatomycosis, including highly keratinized regions as in plantar tinea pedis and palmar tinea manus;
Treatment of pityriasis versicolor;
Treatment of oral candidosis.
Treatment of onychomycosis, caused by dermatophytes and/or yeasts.
Systemic mycoses, only in the following fungal infections: Treatment of systemic aspergillosis and candidosis;
Cryptococcosis (including cryptococcal meningitis): Treatment of immunocompromised patients with cryptococcosis and in all patients with cryptococcosis of the central nervous system, only when first line treatment is considered inappropriate or has proven ineffective;
For maintenance therapy of cryptococcal meningitis in AIDS patients, only when first line treatment is considered inappropriate or has proven ineffective.
Treatment of histoplasmosis;
Histoplasmosis, maintenance therapy only in AIDS patients;
Treatment of blastomycosis;
Treatment of sporotrichosis, including lymphocutaneous/cutaneous and extracutaneous;
Treatment of paracoccidioidomycosis;
Treatment of chromomycosis.
Oral solution: SPORANOX Oral Solution is indicated: For the treatment of oral and/or esophageal candidosis in HIV-positive or other immunocompromised patients.
As prophylaxis of deep fungal infections when standard therapy is considered in appropriate in patients with hematological malignancy or undergoing bone marrow transplant, and who are expected to become neutropenic (i.e., < 500 cells/μL).
At present there are insufficient data on clinical efficacy in the prevention of aspergillosis.

Capsule: For optimal absorption, administer SPORANOX capsules immediately after a full meal.
The capsules must be swallowed whole. (See Table 1, Table 2 and Table 3.)

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Elimination of itraconazole from skin and nail tissue is slower than from plasma. Optimal clinical and mycological response is thus reached 2 to 4 weeks after the cessation of treatment for skin infections and 6 to 9 months after the cessation of treatment for nail infections. (See Table 4.)

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Oral solution: For optimal absorption, SPORANOX Oral Solution should be taken without food (patients are advised to refrain from eating for at least 1 hour after intake).
For the treatment of oral and/or esophageal candidosis, the oral solution should be swished around the oral cavity (approx. 20 seconds) and swallowed. There should be no rinsing after swallowing.
Treatment of oral candidiasis: 200 mg (2 measuring cups, i.e. 20 mL) per day in two intakes, or alternatively in one intake, for 1 week. If there is no response after 1 week, treatment should be continued for another week.
Treatment of esophageal candidosis: 100 mg (1 measuring cup, i.e. 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 (2 measuring cups, i.e. 20 mL) per day may be used based on the clinical response of the patient.
Treatment of fluconazole resistant oral and/or esophageal candidosis: 100 to 200 mg (1 - 2 measuring cups) twice daily for 2 weeks. If there is no response after 2 weeks, treatment should be continued for another 2 weeks. The 400 mg daily dose should not be used for longer than 14 days if there are no signs of improvement.
Prophylaxis of fungal infections: 5 mg/kg per day administered in two intakes. In clinical trials, prophylaxis treatment was started immediately prior to the cytostatic treatment and generally one week before transplant procedure. Treatment was continued until recovery of neutrophils (i.e., > 1000 cells/μL).
Special Populations: Pediatrics: Capsule: Clinical data on the use of SPORANOX capsules in pediatric patients are limited. The use of SPORANOX capsules in pediatric patients is not recommended unless it is determined that the potential benefit outweighs the potential risks. (See Precautions.)
Oral solution: Prophylaxis of fungal infections: there are no efficacy data available in neutropenic children. Limited safety experience is available with a dose of 5 mg/kg per day administered in two intakes. The incidence of adverse events such as diarrhea, abdominal pain, vomiting, fever, rash and mucositis was higher than in adults. However, it is not clear to what extent this is attributable to SPORANOX Oral Solution or the chemotherapy.
Elderly: Clinical data on the use of SPORANOX in elderly patients are limited. It is advised to use SPORANOX in these patients only if it is determined that the potential benefit outweighs the potential risks. In general, it is recommended that the dose selection for an elderly patient should be taken into consideration, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. (See Precautions.)
Hepatic impairment: Limited data are available on the use of oral itraconazole in patients with hepatic impairment. Caution should be exercised when this drug is administered in this patient population. (See Pharmacology: Pharmacokinetics: Special Populations: Hepatic impairment under Actions).
Renal impairment: Limited data are available on the use of oral itraconazole in patients with renal impairment. The exposure of itraconazole may be lower in some patients with renal insufficiency. Caution should be exercised when this drug is administered in this patient population and adjusting the dose may be considered.

Symptoms and signs: In general, adverse events reported with overdose have been consistent with those reported for itraconazole use. (See Adverse Reactions.)
Treatment: In the event of an overdose, supportive measures should be employed.
It is advisable to contact a poison control center to determine the latest recommendations for the management of overdose.
Itraconazole cannot be removed by hemodialysis.
No specific antidote is available.

SPORANOX are contraindicated in patients with known hypersensitivity to itraconazole or to any of the excipients.
Coadministration of a number of CYP3A4 substrates is contraindicated with SPORANOX. Increased plasma concentrations of these drugs, caused by coadministration with itraconazole, may increase or prolong both therapeutic and adverse effects to such an extent that a potentially serious situation may occur. For example, increased plasma concentrations of some of these drugs can lead to QT prolongation and ventricular tachyarrhythmias including occurrences of torsade de pointes, a potentially fatal arrhythmia. Specific examples are listed in Interactions.
SPORANOX 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 Precautions.)
SPORANOX must not be used during pregnancy (except for life-threatening cases). (See Pregnancy, Breast-feeding and Fertility under Use in Pregnancy & Lactation.)
Women of childbearing potential taking SPORANOX should use contraceptive precautions. Effective contraception should be continued until the menstrual period following the end of SPORANOX therapy.

Cardiac effects: In a healthy volunteer study with SPORANOX IV, a transient asymptomatic decrease of the left ventricular ejection fraction was observed; this resolved before the next infusion. The clinical relevance of these findings to the oral formulations is unknown.
Itraconazole has been shown to have a negative inotropic effect and SPORANOX has been associated with reports of congestive heart failure. Heart failure was more frequently reported among spontaneous reports of 400 mg total daily dose than among those of lower total daily doses, suggesting that the risk of heart failure might increase with the total daily dose of itraconazole.
SPORANOX should not be used in patients with congestive heart failure or with a history of congestive heart failure unless the benefit clearly outweighs the risk. This individual benefit/risk assessment should take into consideration factors such as the severity of the indication, the dosing regimen (e.g., total daily dose), and individual risk factors for congestive heart failure. 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 congestive heart failure, should be treated with caution, and should be monitored for signs and symptoms of congestive heart failure during treatment; if such signs or symptoms do occur during treatment, SPORANOX should be discontinued.
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.
Interaction potential: Coadministration of specific drugs with itraconazole may result in changes in efficacy of itraconazole and/or the coadministered drug, life-threatening effects and/or sudden death. Drugs that are contraindicated, not recommended or recommended for use with caution in combination with itraconazole are listed in Interactions.
Cross-hypersensitivity: There is limited information regarding cross-hypersensitivity between itraconazole and other azole antifungal agents. Caution should be used in prescribing SPORANOX to patients with hypersensitivity to other azoles.
Neuropathy: If neuropathy occurs that may be attributable to SPORANOX, 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 Contraindications and Drugs that may have their plasma concentrations increased by itraconazole under Interactions). The hearing loss usually resolves when treatment is stopped, but can persist in some patients.
Cross-resistance: In systemic candidosis, if fluconazole-resistant strains of Candida species are suspected, it cannot be assumed that these are sensitive to itraconazole, hence it is recommended to have their sensitivity tested before the start of itraconazole therapy.
Interchangeability: It is not recommended that SPORANOX capsules and SPORANOX oral solution be used interchangeably. This is because drug exposure is greater with the oral solution than with the capsules when the same dose of drug is given.
Hepatic effects: Very rare cases of serious hepatotoxicity, including some cases of fatal acute liver failure, have occurred with the use of SPORANOX. Most of these cases involved patients who, had pre-existing liver disease, were treated for systemic indications, had significant other medical conditions and/or were taking other hepatotoxic drugs. Some patients had no obvious risk factors for liver disease. Some of these cases were observed within the first month of treatment, including some within the first week. Liver function monitoring should be considered in patients receiving SPORANOX treatment. Patients should be instructed to promptly report to their physician signs and symptoms suggestive of hepatitis such as anorexia, nausea, vomiting, fatigue, abdominal pain or dark urine. In these patients treatment should be stopped immediately and liver function testing should be conducted.
Limited data are available on the use of oral itraconazole in patients with hepatic impairment. Caution should be exercised when the drug is administered in this patient population. It is recommended that patients with impaired hepatic function be carefully monitored when taking itraconazole. It is recommended that the prolonged elimination half-life of itraconazole observed in the single oral dose clinical trial with itraconazole capsules in cirrhotic patients be considered when deciding to initiate therapy with other medications metabolized by CYP3A4.
In patients with elevated or abnormal liver enzymes or active liver disease, or who have experienced liver toxicity with other drugs, treatment with SPORANOX is strongly discouraged unless there is a serious or life threatening situation where the expected benefit exceeds the risk. It is recommended that liver function monitoring be done in patients with pre-existing hepatic function abnormalities or those who have experienced liver toxicity with other medications. (See Pharmacology: Pharmacokinetics: Special Populations: Hepatic impairment under Actions.)
Renal impairment: Limited data are available on the use of oral itraconazole in patients with renal impairment. The exposure of itraconazole may be lower in some patients with renal insufficiency. Caution should be exercised when this drug is administered in this patient population and adjusting the dose may be considered.
Cystic fibrosis: In cystic fibrosis patients, variability in therapeutic levels of itraconazole was observed with steady state dosing of itraconazole oral solution using 2.5 mg/kg bid. Steady state concentrations of > 250 ng/mL were achieved in approximately 50% of subjects greater than 16 years of age, but in none of the patients less than 16 years of age. If a patient does not respond to SPORANOX capsules, consideration should be given to switching to alternative therapy.
Capsule: Reduced gastric acidity: Absorption of itraconazole from SPORANOX capsules is impaired when gastric acidity is reduced. In patients with reduced gastric acidity, whether from disease (e.g. patients with achlorhydria) or from concomitant medication (e.g. patients taking drugs that reduce gastric acidity), it is advisable to administer SPORANOX capsules with an acidic beverage (such as non-diet cola). The antifungal activity should be monitored and the itraconazole dose increased as deemed necessary. (See Drugs that may decrease itraconazole plasma concentrations under Interactions and Pharmacology: Pharmacokinetics: Absorption under Actions.)
Immunocompromised patients: In some immunocompromised patients (e.g., neutropenic, AIDS or organ transplant patients), the oral bioavailability of SPORANOX capsules may be decreased. Therefore, the dose should be adjusted based on the clinical response in these patients.
Patients with immediately life-threatening systemic fungal infections: Due to the pharmacokinetic properties (See Pharmacology: Pharmacokinetics under Actions), SPORANOX capsules are not recommended for initiation of treatment in patients with immediately life-threatening systemic fungal infections.
Patients with AIDS: In patients with AIDS who have received treatment for a systemic fungal infection with SPORANOX capsules and who are considered at risk for relapse, the treating physician should evaluate the need for a maintenance treatment.
Oral solution: Treatment of severely neutropenic patients: SPORANOX Oral Solution as treatment for oral and/or esophageal candidosis was not investigated in severely neutropenic patients. Due to the pharmacokinetic properties (see Pharmacology: Pharmacokinetics under Actions), SPORANOX Oral Solution is not recommended for initiation of treatment in patients at immediate risk of systemic candidosis.
Effects on Ability to Drive and Use Machines: No studies on the effects on the ability to drive and use machines have been performed. When driving vehicles and operating machinery the possibility of adverse reactions such as dizziness, visual disturbances and hearing loss (See Adverse Reactions.), which may occur in some instances, must be taken into account.
Use in Children: Clinical data on the use of SPORANOX capsules in pediatric patients are limited. The use of SPORANOX in pediatric patients is not recommended unless it is determined that the potential benefit outweighs the potential risks.
Use in Elderly: Clinical data on the use of SPORANOX capsules in elderly patients are limited. It is advised to use SPORANOX in these patients only if it is determined that the potential benefit outweighs the potential risks. In general, it is recommended that the dose selection for an elderly patient should be taken into consideration, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Pregnancy: SPORANOX must not be used during pregnancy except for life-threatening cases where the potential benefit to the mother outweighs the potential harm to the fetus (See Contraindications).
In animal studies itraconazole has shown reproduction toxicity (See Pharmacology: Toxicology: Non-Clinical Information under Actions).
There is limited information on the use of SPORANOX during pregnancy. During post-marketing experience, cases of congenital abnormalities have been reported. These cases included skeletal, genitourinary tract, cardiovascular and ophthalmic malformations as well as chromosomal and multiple malformations. A causal relationship with SPORANOX has not been established.
Epidemiological data on exposure to SPORANOX during the first trimester of pregnancy - mostly in patients receiving short-term treatment for vulvovaginal candidosis - did not show an increased risk for malformations as compared to control subjects not exposed to any known teratogens. Itraconazole has been shown to cross the placenta in a rat model.
Women of childbearing potential: Women of childbearing potential taking SPORANOX capsules should use contraceptive precautions. Highly effective contraception should be continued until the menstrual period following the end of SPORANOX therapy.
Breast-feeding: A very small amount of itraconazole is excreted in human milk. The expected benefits of SPORANOX capsules therapy should therefore be weighed against the potential risk of breast-feeding. In case of doubt, the patient should not breast-feed.
Fertility: Capsule: Refer to Pharmacology: Toxicology: Non-Clinical Information under Actions for in animal fertility information relevant to itraconazole.
Oral solution: Refer to Pharmacology: Toxicology: Non-Clinical Information under Actions for in animal fertility information relevant to itraconazole and hydroxypropyl-β-cyclodextrin.

Throughout this section, adverse reactions are presented. Adverse reactions are adverse events that were considered to be reasonably associated with the use of itraconazole based on the comprehensive assessment of the available adverse event information. A causal relationship with itraconazole cannot be reliably established in individual cases. Further, because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.
Clinical trial data: Capsule: The safety of SPORANOX capsules was evaluated in 8499 patients who participated in 107 open-label and double-blind clinical trials. Of the 8499 patients treated with SPORANOX capsules, 2104 patients were treated with SPORANOX capsules during double-blind trials. All 8499 patients received at least one dose of SPORANOX capsules for the treatment of dermatomycoses or onychomycosis and provided safety data. Adverse reactions reported for ≥1% of patients treated with SPORANOX capsules in these clinical trials are shown in Table 5. (See Table 5.)

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Adverse reactions that occurred in <1% of patients treated with SPORANOX capsules in these clinical trials are listed in Table 6. (See Table 6.)

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The following is a list of additional adverse reactions associated with itraconazole that have been reported in clinical trials of SPORANOX oral solution and/or SPORANOX IV, excluding the adverse reaction term "Injection site inflammation" which is specific to the injection route of administration.
Blood and Lymphatic System Disorders: Granulocytopenia, Thrombocytopenia.
Immune System Disorders: Anaphylactoid reaction.
Metabolism and Nutrition Disorders: Hyperglycemia, Hyperkalemia, Hypokalemia, Hypomagnesemia.
Psychiatric Disorders: Confusional state.
Nervous System Disorders: Neuropathy peripheral, Dizziness, Somnolence.
Cardiac Disorders: Cardiac failure, Left ventricular failure, Tachycardia.
Vascular Disorders: Hypertension, Hypotension.
Respiratory, Thoracic and Mediastinal Disorders: Pulmonary edema, Dysphonia, Cough.
Gastrointestinal Disorders: Gastrointestinal disorder.
Hepatobiliary Disorders: Hepatic failure, Hepatitis, Jaundice.
Skin and Subcutaneous Tissue Disorders: Rash erythematous, Hyperhidrosis.
Musculoskeletal and Connective Tissue Disorders: Myalgia, Arthralgia.
Renal and Urinary Disorders: Renal impairment, Urinary incontinence.
General Disorders and Administration Site Conditions: Generalized edema, Face edema, Chest pain, Pyrexia, Pain, Fatigue, Chills.
Investigations: Alanine aminotransferase increased, Aspartate aminotransferase increased, Blood alkaline phosphatase increased, Blood lactate dehydrogenase increased, Blood urea increased, Gamma-glutamyltransferase increased, Hepatic enzyme increased, Urine analysis abnormal.
Pediatrics: The safety of SPORANOX capsules was evaluated in 165 pediatric patients aged 1 to 17 years who participated in 14 clinical trials (4 double-blind, placebo controlled trials; 9 open-label trials; and 1 trial had an open-label phase followed by a double-blind phase). These patients received at least one dose of SPORANOX capsules for the treatment of fungal infections and provided safety data.
Based on pooled safety data from these clinical trials, the commonly reported adverse reactions in pediatric patients were Headache (3.0%), Vomiting (3.0%), Abdominal pain (2.4%), Diarrhea (2.4%), Hepatic function abnormal (1.2%), Hypotension (1.2%), Nausea (1.2%), and Urticaria (1.2%). In general, the nature of adverse reactions in pediatric patients is similar to that observed in adult subjects, but the incidence is higher in the pediatric patients.
Oral solution: The safety of SPORANOX Oral Solution was evaluated in 889 patients who participated in six double-blind and four open-label clinical trials. Of the 889 patients treated with SPORANOX Oral Solution, 624 patients were treated with SPORANOX Oral Solution during the double-blind trials. All 889 patients received at least one dose of SPORANOX Oral Solution for the treatment of oropharyngeal and esophageal candidiasis and provided safety data. Adverse reactions reported for ≥1% of patients treated with SPORANOX Oral Solution in these clinical trials are shown in Table 7. (See Table 7.)

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Adverse reactions that occurred in <1% of patients treated with SPORANOX Oral Solution in these clinical trials are listed in Table 8. (See Table 8.)

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The following is a list of additional adverse reactions associated with itraconazole that have been reported in clinical trials of SPORANOX capsules and/or SPORANOX IV, excluding the adverse reaction term "Injection site inflammation" which is specific to the injection route of administration.
Infections and Infestations: Sinusitis, Upper respiratory tract infection, Rhinitis.
Blood and Lymphatic System Disorders: Granulocytopenia.
Immune System Disorders: Anaphylactoid reaction.
Metabolism and Nutrition Disorders: Hyperglycemia, Hyperkalemia, Hypomagnesemia.
Psychiatric Disorders: Confusional state.
Nervous System Disorders: Somnolence.
Cardiac Disorders: Left ventricular failure, Tachycardia.
Vascular Disorders: Hypertension, Hypotension.
Respiratory, Thoracic and Mediastinal Disorders: Pulmonary edema, Dysphonia.
Gastrointestinal Disorders: Gastrointestinal disorder, Flatulence.
Hepatobiliary Disorders: Hepatitis, Jaundice, Hepatic function abnormal.
Skin and Subcutaneous Tissue Disorders: Rash erythematous, Hyperhidrosis.
Renal and Urinary Disorders: Renal impairment, Pollakiuria, Urinary incontinence.
Reproductive System and Breast Disorders: Erectile dysfunction.
General Disorders and Administration Site Conditions: Generalized edema, Face edema, Chest pain, Pain, Fatigue, Chills.
Investigations: Alanine aminotransferase increased, Aspartate aminotransferase increased, Blood alkaline phosphatase increased, Blood lactate dehydrogenase increased, Blood urea increased, Gamma-glutamyltransferase increased, Hepatic enzyme increased, Urine analysis abnormal.
Pediatrics: The safety of SPORANOX Oral Solution was evaluated in 250 pediatric patients aged 6 months to 14 years who participated in five open-label clinical trials. These patients received at least one dose of SPORANOX Oral Solution for prophylaxis of fungal infections or for treatment of oral thrush or systemic fungal infections and provided safety data.
Based on pooled safety data from these clinical trials, the very common reported adverse reactions in pediatric patients were Vomiting (36.0%), Pyrexia (30.8%), Diarrhea (28.4%), Mucosal inflammation (23.2%), Rash (22.8%), Abdominal pain (17.2%), Nausea (15.6%), Hypertension (14.0%), and Cough (11.2%). The nature of adverse reactions in pediatric patients is similar to that observed in adult subjects, but the incidence is higher in the pediatric patients.
Post-marketing data: In addition to the adverse reactions reported during clinical studies and listed previously, the following adverse reactions have been reported during postmarketing experience (Table 9). The frequencies are provided according to the following convention: Very common ≥1/10; Common ≥1/100 and <1/10; Uncommon ≥1/1000 and <1/100; Rare ≥1/10000 and <1/1000; Very rare <1/10000, including isolated reports.
In Table 9, adverse reactions are presented by frequency category based on spontaneous reporting rates. (See Table 9.)

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Itraconazole is a drug with a high interaction potential. The various types of interaction and associated general recommendations are described as follows. In addition, a table is provided listing examples of drugs that may interact with itraconazole, organized per drug family for easy reference. This list of examples is not comprehensive and therefore the label of each drug that is coadministered with itraconazole should be consulted for information related to the route of metabolism, interaction pathways, potential risks, and specific actions to be taken with regards to coadministration.
Itraconazole is mainly metabolized through CYP3A4. Other substances that either share this metabolic pathway or modify CYP3A4 activity may influence the pharmacokinetics of itraconazole. Coadministration of itraconazole with moderate or potent CYP3A4 inducers may decrease the bioavailability of itraconazole and hydroxy-itraconazole to such an extent that efficacy may be reduced. Coadministration with moderate or potent inhibitors of CYP3A4 may increase the bioavailability of itraconazole, which may result in increased or prolonged pharmacologic effects of itraconazole.
Capsule: Absorption of itraconazole from the capsule formulation is reduced in subjects with reduced gastric acidity. Drugs that reduce gastric acidity impair the absorption of itraconazole from itraconazole capsules. To counteract this effect it is recommended to administer itraconazole capsules with an acidic beverage (such as non-diet cola) upon coadministration with drugs that reduce gastric acidity (see Precautions).
Itraconazole and its major metabolite, hydroxy-itraconazole are potent CYP3A4 inhibitors. Itraconazole is an inhibitor of the drug transporters P-glycoprotein and breast cancer resistance protein (BRCP). Itraconazole can inhibit the metabolism of drugs metabolized by CYP3A4 and can inhibit the drug transport by P-glycoprotein and/or BCRP, which may result in increased plasma concentrations of these drugs and/or their active metabolite(s) when they are administered with itraconazole. These elevated plasma concentrations may increase or prolong both therapeutic and adverse effects of these drugs. For some drugs, coadministration with itraconazole may result in decreased plasma concentrations of the drug or of the active moiety of the drug. This may result in reduced efficacy of the drug.
Following cessation of medical treatment with itraconazole, plasma concentrations decrease below the detection limit within 7 to 14 days, depending on the dose and duration of treatment. In patients with hepatic cirrhosis or in subjects receiving CYP3A4 inhibitors the plasma concentrations decline slower. This is particularly important for consideration when initiating therapy with drugs whose metabolism is affected by itraconazole.
The following general recommendations apply, unless stated differently in Table 10: 'Contraindicated': Under no circumstances is the drug to be coadministered with itraconazole. This applies to: CYP3A4 substrates for which increased plasma concentrations may increase or prolong therapeutic and/or adverse effects to such an extent that a potentially serious situation may occur (see Contraindications).
'Not recommended': It is recommended that the use of the drug be avoided, unless the benefits outweigh the potentially increased risks. If coadministration cannot be avoided, clinical monitoring is recommended, and the dosage of itraconazole and/or the coadministered drug adapted as deemed necessary. When appropriate, it is recommended that plasma concentrations be measured. This applies to: Moderate or potent CYP3A4 inducers: not recommended from 2 weeks before and during treatment with itraconazole.
CYP3A4/P-gp/BCRP substrates for which increased or decreased plasma concentrations result in significant risk: not recommended during and up to 2 weeks after treatment with itraconazole.
'Use with caution': Careful monitoring is recommended when the drug is coadministered with itraconazole. Upon coadministration, it is recommended that patients be monitored closely and the dosage of itraconazole and/or the coadministered drug adapted as deemed necessary. When appropriate, it is recommended that plasma concentrations be measured. This applies to: Drugs that reduce gastric acidity (itraconazole caps only).
Moderate or potent inhibitors of CYP3A4.
CYP3A4/P-gp/BCRP substrates for which increased or decreased plasma concentrations result in a clinically relevant risk.
Examples of interacting drugs are listed in the table as follows. The drugs listed in this table are based on either drug interaction studies or case reports, or potential interactions based on the mechanism of interaction. (See Table 10a, Table 10b, Table 10c, Table 10d and Table 10e)

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Pediatric population: Interaction studies have only been performed in adults.

Instructions for Use and Handling: Capsule: Not applicable.
Oral solution: SPORANOX Oral Solution is supplied in bottles with a childproof cap, and should be opened as follows: push the plastic screw cap down while turning it counter clockwise.
A measuring cup is supplied with the SPORANOX Oral Solution. Use the measuring cup just as it sits on the bottle. Make sure that the side with the graduations (the side that holds less) is uppermost; that is the side you have to fill. When the arrow on the side points up, the correct side is uppermost.
Incompatibilities: None known.

Capsule: Store below 30°C.
Oral Solution: Store at 25°C or below.
Shelf Life: Capsule: 3 years.
Oral Solution: 2 years.
1 month after first opening the container.

Antifungals

J02AC02 - itraconazole ; Belongs to the class of triazole and tetrazole derivatives. Used in the systemic treatment of mycotic infections.

B