Pharmacokinetics and Metabolism:

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 m2, the exposure, based on AUC, was slightly reduced compared with normal population parameters. This study did not demonstrate any significant effect of hemodialysis or continuous ambulatory peritoneal dialysis on the pharmacokinetics of itraconazole (Tmax, Cmax, and AUC0 to 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 to 79 mL/min), moderate (defined in this study as CrCl 20 to 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 to 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 PRECAUTIONS and 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 Cmax (47%) and a twofold increase in the elimination half-life (37 ± 17 hours vs. 16 ± 5 hours) of itraconazole were noted in cirrhotic subjects compared with healthy subjects. However, overall exposure to itraconazole, based on AUC, was similar in cirrhotic patients and in healthy subjects. Data are not available in chornic patients during long-term use of itraconazole. (See CONTRAINDICATIONS, PRECAUTIONS: Drug Interactions and DOSAGE AND ADMINISTRATION.)

Decreased Cardiac Contractility:

When itraconazole was administered intravenously to anesthetized dogs, a dose-related negative inotropic effect was documented. In a healthy volunteer study of itraconazole intravenous infusion, transient, asymptomatic decreases in left ventricular ejection fraction were observed using gated SPECT imaging; these resolved before the next infusion, 12 hours later. If signs or symptoms of congestive heart failure appear during administration of itraconazole oral solution, monitor carefully and consider other treatment alternatives which may include discontinuation of itraconazole oral solution administration. (See BOXED WARNING, CONTRAINDICATIONS, WARNINGS, PRECAUTIONS: Drug Interactions and ADVERSE REACTIONS: Post-marketing Experience for more information.)

Cystic Fibrosis:

Seventeen cystic fibrosis patients, ages 7 to 28 years old, were administered itraconazole oral solution 2.5 mg/kg b.i.d. for 14 days in a pharmacokinetic study. Sixteen patients completed the study. Steady state trough concentrations >250 ng/mL were achieved in 6 out of 11 patients ³16 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 ³16 and <16 years, respectively; %CV for AUC = 75% and 58% for ³16 and <16 years, respectively). If a patient with cystic fibrosis does not respond to itraconazole 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.

Mechanism of Action:

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

Antimicrobial Activity:

Itraconazole has been shown to be active against most strains of the following microorganism, both in vitro and 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 vitro and from patients receiving prolonged therapy.

Candida krusei, Candida glabrata and Candida tropicalis are generally the least susceptible Candida species, with some isolates showing unequivocal resistance to itraconazole in vitro.

Itraconazole is not active against Zygomycetes (e.g., Rhizopus spp., Rhizomucor spp., Mucor spp. and Absidia spp.), Fusarium spp., Scedosporium spp. and Scopulariopsis spp.

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 their sensitivity should be tested before the start of itraconazole therapy.

Several in vitro studies have reported that some fungal clinical isolates, including Candida species, with reduced susceptibility to one azole antifungal agent may also be less susceptible to other azole derivatives. The finding of cross-resistance is dependent on a number of factors, including the species evaluated, its clinical history, the particular azole compounds compared, and the type of susceptibility test that is performed.

Studies (both in vitro and in vivo) suggest that the activity of amphotericin B may be suppressed by prior azole antifungal therapy. As with other azoles, itraconazole inhibits the 14C-demethylation step in the synthesis of ergosterol, a cell wall component of fungi. Ergosterol is the active site for amphotericin B. In one study the antifungal activity of amphotericin B against Aspergillus fumigatus infections in mice was inhibited by ketoconazole therapy. The clinical significance of test results obtained in this study is unknown.

Oropharyngeal Candidiasis:

Two randomized, controlled studies for the treatment of oropharyngeal candidiasis have been conducted (total n = 344). In one trial, clinical response to either 7 or 14 days of itraconazole oral solution, 200 mg/day, was similar to fluconazole tablets and averaged 84% across all arms. Clinical response in this study was defined as cured or improved (only minimal signs and symptoms with no visible lesions). Approximately 5% of subjects were lost to follow-up before any evaluations could be performed. Response to 14 days therapy of itraconazole oral solution was associated with a lower relapse rate than 7 days of itraconazole therapy. In another trial, the clinical response rate (defined as cured or improved) for itraconazole oral solution was similar to clotrimazole troches and averaged approximately 71% across both arms, with approximately 3% of subjects lost to follow-up before any evaluations could be performed. Ninety-two percent of the patients in these studies were HIV seropositive.

In an uncontrolled, open-label study of selected patients clinically unresponsive to fluconazole tablets (n = 74, all patients HIV seropositive), patients were treated with itraconazole oral solution 100 mg b.i.d. (Clinically unresponsive to fluconazole in this study was defined as having received a dose of fluconazole tablets at least 200 mg/day for a minimum of 14 days.) Treatment duration was 14 to 28 days based on response. Approximately 55% of patients had complete resolution of oral lesions. Of patients who responded and then entered a followup phase (n = 22), all relapsed within 1 month (median 14 days) when treatment was discontinued. Although baseline endoscopies had not been performed, several patients in this study developed symptoms of esophageal candidiasis while receiving therapy with itraconazole oral solution. Itraconazole oral solution has not been directly compared to other agents in a controlled trial of similar patients.

Esophageal Candidiasis:

A double-blind randomized study (n = 119, 111 of whom were HIV seropositive) compared itraconazole oral solution (100 mg/day) to fluconazole tablets (100 mg/day). The dose of each was increased to 200 mg/day for patients not responding initially. Treatment continued for 2 weeks following resolution of symptoms, for a total duration of treatment of 3 to 8 weeks. Clinical response (a global assessment of cured or improved) was not significantly different between the two study arms, and averaged approximately 86% with 8% lost to follow-up. Six of 53 (11%) itraconazole-treated patients and 12/57 (21%) fluconazole-treated patients were escalated to the 200 mg dose in this trial. Of the subgroup of patients who responded and entered a follow-up phase (n = 88), approximately 23% relapsed across both arms within 4 weeks.

Congestive Heart Failure:

Itraconazole oral solution should not be administered to patients with evidence of ventricular dysfunction such as congestive heart failure (CHF) or a history of CHF except for the treatment of life-threatening or other serious infections. (See BOXED WARNING, WARNINGS, PRECAUTIONS: Drug Interactions-Calcium Channel Blockers, ADVERSE REACTIONS: Post-marketing Experience, and CLINICAL PHARMACOLOGY: Special Populations.)

Drug Interactions:

Coadministration of a number of CYP3A4 substrates are contraindicated with itraconazole. Plasma concentrations increase for the following drugs: levaceytlmethadol (levomethadyl), 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. In addition, coadministration with colchicine, fesoterodine, and solifenacin is contraindicated in subjects with varying degrees of renal or hepatic impairment, and coadministration with eliglustat is contraindicated in subjects that are poor or intermediate metabolizers of CYP2D6 and in subjects taking strong or moderate CYP2D6 inhibitors. (See PRECAUTIONS: Drug Interactions Section for specific examples.) This increase in drug concentrations caused by coadministration with itraconazole 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 torsade de pointes, a potentially fatal arrhythmia. Specific examples are listed in PRECAUTIONS: Drug Interactions.

Itraconazole is contraindicated for patients who have shown hypersensitivity to itraconazole. There is limited information regarding cross-hypersensitivity between itraconazole and other azole antifungal agents. Caution should be used when prescribing itraconazole to patients with hypersensitivity to other azoles.

Hepatic Effects:

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 itraconazole use or reinstitution of treatment with itraconazole is strongly discouraged unless there is a serious or life-threatening situation where the expected benefit exceeds the risk. (See PRECAUTIONS: Information for Patients and ADVERSE REACTIONS.)

Cardiac Dysrhythmias:

Life-threatening cardiac dysrhythmias and/or sudden death have occurred in patients using drugs such as cisapride, pimozide, methadone, or quinidine concomitantly with itraconazole and/or other CYP3A4 inhibitors. Concomitant administration of these drugs with itraconazole oral solution is contraindicated. (See BOXED WARNING, CONTRAINDICATIONS, and PRECAUTIONS: Drug Interactions.)

Cardiac Disease:

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 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 itraconazole oral solution, monitor carefully and consider other treatment alternatives which may include discontinuation of 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.

Itraconazole oral solution 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 itraconazole 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: Postmarketing Experience for more information.)

Interaction potential:

Itraconazole 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:

Itraconazole oral solution and itraconazole 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 itraconazole oral solution has been demonstrated effective for oral and/or esophageal candidiasis.

Hydroxypropyl-β-cyclodextrin:

Itraconazole 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:

Itraconazole oral solution as treatment for oropharyngeal and/or esophageal candidiasis was not investigated in severely neutropenic patients. Due to its pharmacokinetic properties, itraconazole oral solution is not recommended for initiation of treatment in patients at immediate risk of systemic candidiasis.

Hepatotoxicity:

Rare cases of serious hepatotoxicity have been observed with itraconazole treatment, including some cases within the first week. It is recommended that liver function monitoring be considered in all patients receiving itraconazole. 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 itraconazole oral solution, the treatment should be discontinued.

Cystic Fibrosis:

If a patient with cystic fibrosis does not respond to itraconazole 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 Interactions and PRECAUTIONS: Drug Interactions). The hearing loss usually resolves when treatment is stopped, but can persist in some patients.

Information for Patients:

• Only itraconazole oral solution has been demonstrated effective for oral and/or esophageal candidiasis.
• Itraconazole 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 itraconazole oral solution under fasted conditions improves the systemic availability of itraconazole. Instruct patients to take itraconazole oral solution without food, if possible.
• Itraconazole oral solution should not be used interchangeably with itraconazole capsules.
• Instruct patients about the signs and symptoms of congestive heart failure, and if these signs or symptoms occur during itraconazole administration, they should discontinue itraconazole and contact their healthcare provider immediately.
• Instruct patients to stop itraconazole 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 Itraconazole 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, itraconazole 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 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 itraconazole.

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 itraconazole.

Effect of Other Drugs on Itraconazole

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 itraconazole resulting in either increased or sometimes decreased concentrations of itraconazole. Increased concentrations may increase the risk of adverse reactions associated with itraconazole. Decreased concentrations may reduce itraconazole efficacy.

The table below lists examples of drugs that may affect itraconazole concentrations, but 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 itraconazole.

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 itraconazole.

Pediatric Population

Interaction studies have only been performed in adults.

Carcinogenesis, Mutagenesis, and Impairment of Fertility:

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 to 160 mg/kg/day (5 to 20 times the MRHD), and in mice at dosage levels of approximately 80 mg/kg/day (10 times the MRHD). 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.

Itraconazole 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. Itraconazole should be used in pregnancy only if the benefit outweighs the potential risk. Highly effective contraception should be continued throughout itraconazole 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 itraconazole 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 itraconazole 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 (2.5 times the 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 (10 times the MRHD) over 1 year or 160 mg/kg/day (20 times the MRHD) for 6 months, itraconazole induced small tooth pulp with hypocellular appearance in some rats.

Geriatric Use:

Clinical studies of itraconazole 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 itraconazole 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 Interactions and 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 Populations and 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 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 itraconazole 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 preexisting hepatic function abnormalities or those who have experienced liver toxicity with other medications. (See CLINICAL PHARMACOLOGY: Special Populations and DOSAGE AND ADMINISTRATION.)

Adverse Events Reported in Oropharyngeal or Esophageal Candidiasis Trials

U.S. adverse experience data are derived from 350 immunocompromised patients (332 HIV seropositive/AIDS) treated for oropharyngeal or esophageal candidiasis. Table 3 below lists adverse events reported by at least 2% of patients treated with 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 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 Events Reported from Other Clinical Trials

A comparative clinical trial in patients who received intravenous itraconazole followed by itraconazole oral solution or received Amphotericin B reported the following adverse events in the itraconazole intravenous/itraconazole oral solution treatment arm which are not listed above in the subsection “Adverse Events Reported in Oropharnyngeal or Esophageal Candidiasis Trials” or listed below as postmarketing reports of adverse drug reactions: serum creatinine increased, blood urea nitrogen increased, renal function abnormal, hypocalcemia, hypomagnesemia, hypophosphatemia, hypotension, tachycardia and pulmonary infiltration.

In addition, the following adverse drug reactions were reported in patients who participated in itraconazole oral solution clinical trials:

Cardiac Disorders: cardiac failure;

General Disorders and Administration Site Conditions: edema;

Hepatobiliary Disorders: hepatic failure, hyperbilirubinemia;

Metabolism and Nutrition Disorders: hypokalemia;

Reproductive System and Breast Disorders: menstrual disorder

The following is a list of additional adverse drug reactions associated with itraconazole that have been reported in clinical trials of itraconazole capsules and itraconazole IV excluding the adverse reaction term “Injection site inflammation” which is specific to the injection route of administration:

Cardiac Disorders: left ventricular failure;

Gastrointestinal Disorders: gastrointestinal disorder;

General Disorders and Administration Site Conditions: face edema;

Hepatobiliary Disorders: jaundice, hepatic function abnormal;

Investigations: alanine aminotransferase increased, aspartate aminotransferase increased, blood alkaline phosphatase increased, blood lactate dehydrogenase increased, gamma-glutamyltransferase increased, urine analysis abnormal;

Metabolism and Nutrition Disorders: hyperglycemia, hyperkalemia;

Nervous System Disorders: somnolence;

Psychiatric Disorders: confusional state;

Renal and Urinary Disorders: renal impairment;

Respiratory, Thoracic and Mediastinal Disorders: dysphonia;

Skin and Subcutaneous Tissue Disorders: rash erythematous;

Vascular Disorders: hypertension

In addition, the following adverse drug reaction was reported in children only who participated in itraconazole oral solution clinical trials: mucosal inflammation.

Post-marketing Experience

Adverse drug reactions that have been first identified during post-marketing experience with itraconazole (all formulations) are listed in Table 4 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 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 itraconazole has not been established. (See CLINICAL PHARMACOLOGY: Special Populations, CONTRAINDICATIONS, WARNINGS, and PRECAUTIONS: Drug Interactions for more information.)

Treatment of Oropharyngeal and Esophageal Candidiasis:

The solution should be vigorously swished in the mouth (10 mL at a time) for several seconds and swallowed.

The recommended dosage of 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 responding to thera 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 itraconazole oral solution are available at this time.

The recommended dosage of 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.

Itraconazole oral solution and itraconazole capsules should not be used interchangeably. Patients should be instructed to take itraconazole oral solution without food, if possible. Only 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. (See CLINICAL PHARMACOLOGY: Special Populations and PRECAUTIONS.)

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. (See CLINICAL PHARMACOLOGY: Special Populations, WARNINGS, and PRECAUTIONS.)