CLINICAL PHARMACOLOGY SECTION

CLINICAL PHARMACOLOGY

Pharmacokinetics and Metabolism

Itraconazole

General Pharmacokinetic Characteristics

Peak plasma concentrations are reached within 2.5 hours following administration of the oral solution. 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 maxand AUC values 4 to 7-fold higher than those seen after a single dose. Steady-state C maxvalues of about 2 µg/mL are reached after oral administration of 200 mg once daily. 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

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 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 WARNINGS.)

Distribution

Most of the itraconazole in plasma is bound to protein (99.8%), with albumin being the main binding component (99.6% for the hydroxy-metabolite). It has also a marked affinity for lipids. Only 0.2% of the itraconazole in plasma is present as free drug. Itraconazole is distributed in a large apparent volume in the body (>700 L), suggesting extensive distribution into tissues. Concentrations in lung, kidney, liver, bone, stomach, spleen and muscle were found to be two to three times higher than corresponding concentrations in plasma, and the uptake into keratinous tissues, skin in particular, up to four times higher. Concentrations in the cerebrospinal fluid are much lower than in plasma.

Metabolism

Itraconazole is extensively metabolized by the liver into a large number of metabolites. In vitrostudies have shown that CYP3A4 is the major enzyme involved in the metabolism of itraconazole. The main metabolite is hydroxy- itraconazole, which has in vitroantifungal 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.

Special Populations

Renal Impairment

Limited data are available on the use of oral itraconazole in patients with renal impairment. A pharmacokinetic study using a single 200 mg oral dose of itraconazole was conducted in three groups of patients with renal impairment (uremia: n = 7; hemodialysis: n = 7; and continuous ambulatory peritoneal dialysis: n = 5). In uremic subjects with a mean creatinine clearance of 13 mL/min.×1.73 m 2, 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 in renally impaired patients during long-term use of itraconazole. Dialysis has no effect on the half-life or clearance of itraconazole or hydroxy-itraconazole. (See PRECAUTIONSand DOSAGE AND ADMINISTRATION.)

Hepatic Impairment

Itraconazole is predominantly metabolized in the liver. A pharmacokinetic study was conducted in 6 healthy and 12 cirrhotic subjects who were administered a single 100 mg dose of itraconazole as capsule. A statistically significant reduction in mean 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 CONTRAINDICATIONS, PRECAUTIONS: Drug Interactionsand 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 BOXED WARNING, CONTRAINDICATIONS, WARNINGS, PRECAUTIONS: Drug Interactionsand ADVERSE REACTIONS: Post-marketing Experiencefor 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.

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.

MICROBIOLOGY

Mechanism of Action

In vitrostudies have demonstrated that itraconazole inhibits the cytochrome P450-dependent synthesis of ergosterol, which is a vital component of fungal cell membranes.

Antimicrobial Activity

Itraconazole has been shown to be active against most strains of the following microorganism, both in vitroand in clinical infections.

Candida albicans

Susceptibility Testing Methods

For specific information regarding susceptibility test interpretive criteria and associated test methods and quality control standards recognized by FDA for this drug, please see: https://www.fda.gov/STIC.

Drug Resistance

Isolates from several fungal species with decreased susceptibility to itraconazole have been isolated in vitroand from patients receiving prolonged therapy.

Candida krusei, Candida glabrataand Candida tropicalisare generally the least susceptible Candidaspecies, with some isolates showing unequivocal resistance to itraconazole in vitro.

Itraconazole is not active against Zygomycetes(e.g., Rhizopusspp., Rhizomucorspp., Mucorspp. and Absidiaspp.), Fusariumspp., Scedosporiumspp. and Scopulariopsisspp.

Cross-Resistance

In systemic candidosis, if fluconazole-resistant strains of Candidaspecies are suspected, it cannot be assumed that these are sensitive to itraconazole, hence their sensitivity should be tested before the start of itraconazole therapy.

Several in vitrostudies have reported that some fungal clinical isolates, including Candidaspecies, 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.

Studies (both in vitroand 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 fumigatusinfections in mice was inhibited by ketoconazole therapy. The clinical significance of test results obtained in this study is unknown.

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INDICATIONS & USAGE SECTION

INDICATIONS AND USAGE

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 Experiencefor more information.)

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WARNINGS SECTION

WARNINGS

Hepatic Effects

SPORANOX ®has been associated with rare cases of serious hepatotoxicity, including liver failure and death. Some of these cases had neither pre- existing liver disease nor a serious underlying medical condition, and some of these cases developed within the first week of treatment. If clinical signs or symptoms develop that are consistent with liver disease, treatment should be discontinued and liver function testing performed. Continued SPORANOX ®use or reinstitution of treatment with SPORANOX ®is strongly discouraged unless there is a serious or life-threatening situation where the expected benefit exceeds the risk. (See PRECAUTIONS: Information for Patientsand ADVERSE REACTIONS.)

Cardiac Dysrhythmias

Life-threatening cardiac dysrhythmias and/or sudden death have occurred in patients using drugs such as cisapride, pimozide, methadone, or quinidine concomitantly with SPORANOX ®and/or other CYP3A4 inhibitors. Concomitant administration of these drugs with SPORANOX ®is contraindicated. (See BOXED 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 felodipine or nisoldipine is contraindicated.

Cases of CHF, peripheral edema, and pulmonary edema have been reported in the post-marketing period among patients being treated for onychomycosis and/or systemic fungal infections. (See CONTRAINDICATIONS, CLINICAL PHARMACOLOGY: Special Populations, PRECAUTIONS: Drug Interactions, and ADVERSE REACTIONS: Post-marketing Experiencefor more information.)

Interaction Potential

SPORANOX ®has a potential for clinically important drug interactions. Coadministration of specific drugs with itraconazole may result in changes in efficacy of itraconazole and/or the coadministered drug, life-threatening effects and/or sudden death. Drugs that are contraindicated, not recommended or recommended for use with caution in combination with itraconazole are listed in PRECAUTIONS: Drug Interactions.

Interchangeability

SPORANOX ®(itraconazole) Oral Solution and SPORANOX ®Capsules should not be used interchangeably. This is because drug exposure is greater with the Oral Solution than with the Capsules when the same dose of drug is given. Only SPORANOX ®Oral Solution has been demonstrated effective for oral and/or esophageal candidiasis.

Hydroxypropyl-β-cyclodextrin

SPORANOX ®Oral Solution contains the excipient hydroxypropyl-β-cyclodextrin which produced adenocarcinomas in the large intestine and exocrine pancreatic adenocarcinomas in a rat carcinogenicity study. These findings were not observed in a similar mouse carcinogenicity study. The clinical relevance of these adenocarcinomas is unknown. (See PRECAUTIONS: Carcinogenesis, Mutagenesis, and Impairment of Fertility.)

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.

BOXED WARNING SECTION

BOXED WARNING

Congestive Heart Failure, Cardiac Effects and Drug Interactions

Congestive Heart Failure and Cardiac Effects

If signs or symptoms of congestive heart failure occur during administration of SPORANOX*®(itraconazole) Oral Solution, continued SPORANOX®use should be reassessed. *When itraconazole was administered intravenously to dogs and healthy human volunteers, negative inotropic effects were seen. (SeeCONTRAINDICATIONS****,WARNINGS,PRECAUTIONS: Drug Interactions,ADVERSE REACTIONS: Post-marketing Experience, andCLINICAL PHARMACOLOGY: Special Populationsfor more information.)**

Drug Interactions

Coadministration of a number of CYP3A4 substrates are contraindicated with SPORANOX*®. Some examples of drugs that are contraindicated for coadministration with SPORANOX®Oral Solution are: methadone, disopyramide, dofetilide, dronedarone, quinidine, isavuconazole, ergot alkaloids (such as dihydroergotamine, ergometrine (ergonovine), ergotamine, methylergometrine (methylergonovine)), irinotecan, lurasidone, oral midazolam, pimozide, triazolam, felodipine, nisoldipine, ivabradine, ranolazine, eplerenone, cisapride, naloxegol, lomitapide, lovastatin, simvastatin, avanafil, ticagrelor, finerenone, voclosporin. *Coadministration with colchicine, fesoterodine and solifenacin is contraindicated in subjects with varying degrees of renal or hepatic impairment. *Coadministration with eliglustat is contraindicated in subjects that are poor or intermediate metabolizers of CYP2D6 and in subjects taking strong or moderate CYP2D6 inhibitors. *Coadministration with venetoclax is contraindicated in patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) during the dose initiation and ramp-up phase of venetoclax. SeePRECAUTIONS: Drug InteractionsSection for specific examples.** Coadministration with itraconazole can cause elevated plasma concentrations of these drugs and may increase or prolong both the pharmacologic effects and/or adverse reactions to these drugs. For example, increased plasma concentrations of some of these drugs can lead to QT prolongation and ventricular tachyarrhythmias including occurrences of torsades de pointes, a potentially fatal arrhythmia. See**CONTRAINDICATIONSandWARNINGSSections, and**PRECAUTIONS: Drug Interactions*Section for specific examples.

PRECAUTIONS SECTION

PRECAUTIONS

Hepatotoxicity

Rare cases of serious hepatotoxicity have been observed with SPORANOX ®treatment, including some cases within the first week. It is recommended that liver function monitoring be considered in all patients receiving SPORANOX ®. Treatment should be stopped immediately and liver function testing should be conducted in patients who develop signs and symptoms suggestive of liver dysfunction.

Neuropathy

If neuropathy occurs that may be attributable to SPORANOX ®Oral Solution, the treatment should be discontinued.

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).

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 BOXED WARNING: Drug Interactions, CONTRAINDICATIONS: Drug Interactionsand 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 adenocarcinomas in the large intestine and exocrine pancreatic adenocarcinomas in a rat carcinogenicity study. These findings were not observed in a similar mouse carcinogenicity study. The clinical relevance of these adenocarcinomas 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.
• Instruct patients that dizziness or blurred/double vision can sometimes occur with itraconazole. Advise patients that if they experience these events, they should not drive or use machines.

Drug Interactions

Effect of SPORANOX ®on Other Drugs

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 (BCRP). Consequently, SPORANOX ®has the potential to interact with many concomitant drugs resulting in either increased or sometimes decreased concentrations of the concomitant drugs. Increased concentrations may increase the risk of adverse reactions associated with the concomitant drug which can be severe or life-threatening in some cases (e.g., QT prolongation, Torsade de Pointes, respiratory depression, hepatic adverse reactions, hypersensitivity reactions, myelosuppression, hypotension, seizures, angioedema, atrial fibrillation, bradycardia, priapism). Reduced concentrations of concomitant drugs may reduce their efficacy. The table below lists examples of drugs that may have their concentrations affected by itraconazole, but it is not a comprehensive list.

Refer to the approved product labeling to become familiar with the interaction pathways risk, potential and specific actions to be taken with regards to each concomitant drug prior to initiating therapy with SPORANOX ®.

Although many of the clinical drug interactions in Table 1 below are based on information with a similar azole antifungal, ketoconazole, these interactions are expected to occur with SPORANOX ®.

Table 1: Drug Interactions with SPORANOX ®that Affect Concomitant Drug Concentrations

Effect of Other Drugs on SPORANOX ®

Itraconazole is mainly metabolized through CYP3A4. Other substances that either share this metabolic pathway or modify CYP3A4 activity may influence the pharmacokinetics of itraconazole. Some concomitant drugs have the potential to interact with SPORANOX ®resulting in either increased or sometimes decreased concentrations of SPORANOX ®. Increased concentrations may increase the risk of adverse reactions associated with SPORANOX ®. Decreased concentrations may reduce SPORANOX ®efficacy.

The table below lists examples of drugs that may affect itraconazole concentrations, but it is not a comprehensive list. Refer to the approved product labeling to become familiar with the interaction pathways, risk potential and specific actions to be taken with regards to each concomitant drug prior to initiating therapy with SPORANOX ®.

Although many of the clinical drug interactions in Table 2 below are based on information with a similar azole antifungal, ketoconazole, these interactions are expected to occur with SPORANOX ®.

Table 2: Drug Interactions with Other Drugs that Affect SPORANOX ®Concentrations

Pediatric Population

Interaction studies have only been performed in adults.

Carcinogenesis, Mutagenesis, and Impairment of Fertility

Itraconazole

Itraconazole showed no evidence of carcinogenicity potential in mice treated orally for 23 months at dosage levels up to 80 mg/kg/day (approximately 1 time the maximum recommended human dose [MRHD] of 400 mg/day based on body surface area comparisons). Male rats treated with 25 mg/kg/day (0.6 times the MRHD based on body surface area comparisons) 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 (1.2 times the MRHD based on body surface area comparisons) 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.

Itraconazole produced no mutagenic effects when assayed in DNA repair test (unscheduled DNA synthesis) in primary rat hepatocytes, in Ames tests with Salmonella typhimurium(6 strains) and Escherichia coli, in the mouse lymphoma gene mutation tests, in a sex-linked recessive lethal mutation ( Drosophila melanogaster) 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 (1 time the MRHD based on body surface area comparisons), 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 (4 times the MRHD based on body surface area comparisons).

Hydroxypropyl-β-cyclodextrin (HP-β-CD)

Hydroxypropyl-β-cyclodextrin (HP-β-CD) is the solubilizing excipient used in SPORANOX ®Oral Solution.

Hydroxypropyl-β-cyclodextrin (HP-β-CD) was found to produce neoplasms in the large intestine at 5000 mg/kg/day in rat carcinogenicity study. This dose was about 3 times amount contained in the recommended clinical dose of SPORANOX ®Oral Solution (16 g) based on body surface area comparisons. The clinical relevance of this finding is unknown. 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.

In addition, HP-β-CD 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. The maximum recommended clinical dose of SPORANOX ®Oral Solution contains approximately 3.3 times the amount of HP-β-CD as was in the 500 mg/kg/day dose, based on body surface area comparisons. This finding was not observed in the mouse carcinogenicity study at doses of 500, 2000 or 5000 mg/kg/day for 22–23 months. This finding was also not observed in a 12-month toxicity study in dogs or in a 2-year toxicity study in female cynomolgus monkeys.

Since the development of the pancreatic tumors may be related to a mitogenic action of cholecystokinin and since there is no evidence that cholecystokinin has a mitogenic action in man, the clinical relevance of these findings is unknown.

HP-β-CD has no antifertile effect, and is not mutagenic.

Pregnancy

Teratogenic Effects

Itraconazole was found to cause a dose-related increase in maternal toxicity, embryotoxicity, and teratogenicity in rats at dosage levels of approximately 40–160 mg/kg/day (1–4 times the MRHD based on body surface area comparisons), and in mice at dosage levels of approximately 80 mg/kg/day (1 time the MRHD based on body surface area comparisons). Itraconazole has been shown to cross the placenta in a rat model. In rats, the teratogenicity consisted of major skeletal defects; in mice, it consisted of encephaloceles and/or macroglossia.

SPORANOX ®Oral Solution contains the excipient hydroxypropyl-β-cyclodextrin (HP-β-CD). HP-β-CD has no direct embryotoxic and no teratogenic effect.

There are no studies in pregnant women. SPORANOX ®should be used in pregnancy only if the benefit outweighs the potential risk. Highly effective contraception should be continued throughout SPORANOX ®therapy and for 2 months following the end of treatment.

During post-marketing experience, cases of congenital abnormalities have been reported. (See ADVERSE REACTIONS: Post-marketing Experience.)

Nursing Mothers

Itraconazole is excreted in human milk; therefore, the expected benefits of SPORANOX ®therapy for the mother should be weighed against the potential risk from exposure of itraconazole to the infant. The U.S. Public Health Service Centers for Disease Control and Prevention advises HIV-infected women not to breast-feed to avoid potential transmission of HIV to uninfected infants.

Pediatric Use

The efficacy and safety of SPORANOX ®have not been established in pediatric patients.

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 (0.5 times the MRHD of 400 mg based on body surface area comparisons). 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 (2 times the MRHD based on body surface area comparisons) over 1 year or 160 mg/kg/day (4 times the MRHD based on body surface area comparisons) for 6 months, itraconazole induced small tooth pulp with hypocellular appearance in some rats.

Geriatric Use

Clinical studies of SPORANOX ®Oral Solution did not include sufficient numbers of subjects aged 65 years and over to determine whether they respond differently from younger subjects. It is advised to use SPORANOX ®Oral Solution 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.

Transient or permanent hearing loss has been reported in elderly patients receiving treatment with itraconazole. Several of these reports included concurrent administration of quinidine which is contraindicated (see BOXED WARNING: Drug Interactions, CONTRAINDICATIONS: Drug Interactionsand PRECAUTIONS: Drug Interactions).

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 impairment. Caution should be exercised when itraconazole is administered in this patient population and dose adjustment may be needed. (See CLINICAL PHARMACOLOGY: Special Populationsand DOSAGE AND ADMINISTRATION.)

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. It is recommended that patients with impaired hepatic function be carefully monitored when taking SPORANOX ®. 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 CLINICAL PHARMACOLOGY: Special Populationsand DOSAGE AND ADMINISTRATION.)

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OVERDOSAGE SECTION

OVERDOSAGE

Itraconazole is not removed by dialysis. In the event of accidental overdosage, supportive measures should be employed. Contact a certified poison control center for the most up to date information on the management of SPORANOX ®(itraconazole) Oral Solution overdosage (1-800-222-1222 or www.poison.org). In general, adverse events reported with overdose have been consistent with adverse drug reactions already listed in this package insert for itraconazole. (See ADVERSE REACTIONS.)

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SPL UNCLASSIFIED SECTION

Revised: 03/2024

© 2023 Janssen Pharmaceutical Companies

Manufactured for:

Janssen Pharmaceuticals, Inc.

Titusville, NJ 08560, USA

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