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Itraconazole Oral Solution

TABLE OF CONTENTS

1. DESCRIPTION 7. WARNINGS AND PRECAUTIONS
2. INDICATIONS AND USAGE 8. ADVERSE REACTIONS
3. DOSAGE AND ADMINISTRATION 9. OVERDOSAGE
4. CONTRAINDICATIONS 10. DRUG INTERACTIONS
5. MECHANISM OF ACTION 11. PHARMACOKINETICS
6. USE IN SPECIFIC POPULATIONS 12. HOW SUPPLIED/STORAGE AND HANDLING

 


Congestive Heart Failure, Cardiac Effects and Drug Interactions: When itraconazole was administered intravenously to dogs and healthy human volunteers, negative inotropic effects were seen. If signs or symptoms of congestive heart failure occur during administration of itraconazole oral solution, continued itraconazole use should be reassessed (See CONTRAINDICATIONS, WARNINGS, PRECAUTIONS: Drug Interactions, ADVERSE REACTIONS: Post-marketing Experience).

Drug Interactions: Coadministration of cisapride, oral midazolam, nisoldipine, felodipine, pimozide, quinidine, dofetilide, triazolam, levacetylmethadol (levomethadyl), lovastatin, simvastatin, ergot alkaloids such as dihydroergotamine, ergometrine (ergonovine), ergotamine and methylergometrine (methylergonovine) or methadone with itraconazole capsules or oral solution is contraindicated. Itraconazole, a potent cytochrome P450 3A4 isoenzyme system (CYP3A4) inhibitor, may increase plasma concentrations of drugs metabolized by this pathway. Serious cardiovascular events, including QT prolongation, torsades de pointes, ventricular tachycardia, cardiac arrest, and/or sudden death have occurred in patients using cisapride, pimozide, levacetylmethadol (levomethadyl), or quinidine concomitantly with itraconazole and/or other CYP3A4 inhibitors (See CONTRAINDICATIONS, WARNINGS, and PRECAUTIONS: Drug Interactions for more information.)


 

1. DESCRIPTION

Itraconazole is a synthetic triazole antifungal agent. Itraconazole is a 1:1:1:1 racemic mixture of four diastereomers (two enantiomeric pairs), each possessing three chiral centers. It may be represented by the following structural formula:

Itraconazole has a molecular formula of C35H38Cl2N8O4 and a molecular weight of 705.64. It is a white to slightly yellowish powder. It is insoluble in water, very slightly soluble in alcohols, and freely soluble in dichloromethane. It has a pKa of 3.70 (based on extrapolation of values obtained from methanolic solutions) and a log (n-octanol/water) partition coefficient of 5.66 at pH 8.1.

Itraconazole oral solution contains 10 mg of itraconazole per mL, solubilized by hydroxypropyl-β-cyclodextrin (400 mg/mL) as a molecular inclusion complex. Itraconazole oral solution is clear and yellowish in color with a target pH of 2. Other ingredients are hydrochloric acid, propylene glycol, purified water, sodium hydroxide, sodium saccharin, sorbitol, cherry flavor 1, cherry flavor 2 and caramel flavor.

2. INDICATIONS AND USAGE

Itraconazole oral solution is indicated for the treatment of oropharyngeal and esophageal candidiasis.

3. DOSAGE AND ADMINISTRATION

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) twice daily. For patients responding to therapy, clinical response will be seen in 2 to 4 weeks. Patients may be expected to relapse shortly after discontinuing therapy. Limited data on the safety of long-term use (>6 months) of 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 judgement 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 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 Special Populations and PRECAUTIONS.)

4. CONTRAINDICATIONS

Congestive Heart Failure: Itraconazole oral solution should not be administered for the treatment of onychomycosis in patients with evidence of ventricular dysfunction such as congestive heart failure (CHF) or a history of CHF. (See WARNINGS, PRECAUTIONS: Drug Interactions-Calcium Channel Blockers, and ADVERSE REACTIONS: Postmarketing Experience.)

Drug Interactions: Concomitant administration of itraconazole capsules, injection, or oral solution and certain drugs metabolized by the cytochrome P450 3A4 isoenzyme system (CYP3A4) may result in increased plasma concentrations of those drugs, leading to potentially serious and/or life-threatening adverse events. Cisapride, oral midazolam, nisoldipine, pimozide, quinidine, dofetilide, triazolam and levacetylmethadol (levomethadyl) are contraindicated with itraconazole. HMG CoA-reductase inhibitors metabolized by CYP3A4, such as lovastatin and simvastatin, are also contraindicated with itraconazole. Ergot alkaloids metabolized by CYP3A4 such as dihydroergotamine, ergometrine (ergonovine), ergotamine and methylergometrine (methylergonovine) are contraindicated with itraconazole. (See BOX WARNING, and PRECAUTIONS: Drug Interactions.)

Itraconazole should not be administered for the treatment of onychomycosis to pregnant patients or to women contemplating pregnancy.

Itraconazole is contraindicated for patients who have shown hypersensitivity to itraconazole or its excipients. There is no information regarding cross-hypersensitivity between itraconazole and other azole antifungal agents. Caution should be used when prescribing itraconazole to patients with hypersensitivity to other azoles.

5. 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.

6. USE IN SPECIFIC POPULATIONS

6.1 Usage in Pregnancy

Pregnancy Category C

There are no studies in pregnant women. Itraconazole should be used for the treatment of systemic fungal infections in pregnancy only if the benefit outweighs the potential risk.

Itraconazole should not be administered for the treatment of onychomycosis to pregnant patients or to women contemplating pregnancy. Itraconazole should not be administered to women of childbearing potential for the treatment of onychomycosis unless they are using effective measures to prevent pregnancy and they begin therapy on the second or third day following the onset of menses. 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 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.

6.2 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.

6.3 Pediatric Use

The efficacy and safety of itraconazole have not been established in pediatric patients. No pharmacokinetic data on itraconazole capsules are available in children. A small number of patients ages 3 to 16 years have been treated with 100 mg/day of itraconazole capsules for systemic fungal infections, and no serious unexpected adverse events have been reported. Itraconazole oral solution (5 mg/kg/day) has been administered to pediatric patients (N=26; ages 6 months to 12 years) for 2 weeks and no serious unexpected adverse events were reported.

The long-term effects of itraconazole on bone growth in children are unknown.

6.4 Geriatric Use

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 BOX WARNING: Drug Interactions, CONTRAINDICATIONS: Drug Interactions and PRECAUTIONS: Drug Interactions). Itraconazole should be used with care in elderly patients (see PRECAUTIONS).

6.5 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.

6.6 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.

7. WARNINGS AND PRECAUTIONS

WARNINGS

Itraconazole oral solution and itraconazole capsules should not be used interchangeably. 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 pancreatic adenocarcinomas in a rat carcinogenicity study. These findings were not observed in a similar mouse carcinogenicity study. The clinical relevance of these findings is unknown.

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.

Cardiac Dysrhythmias: Life-threatening cardiac dysrhythmias and/or sudden death have occurred in patients using cisapride, pimozide, levacetylmethadol (levomethadyl), or quinidine concomitantly with itraconazole and/or other CYP3A4 inhibitors. Concomitant administration of these drugs with itraconazole is contraindicated. (See BOX WARNING, CONTRAINDICATIONS, and PRECAUTIONS: Drug Interactions.)

Cardiac Disease: Itraconazole capsules should not be administered for the treatment of onychomycosis in patients with evidence of ventricular dysfunction such as congestive heart failure (CHF) or a history of CHF. Itraconazole capsules should not be used for other indications 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 capsules, discontinue administration.

When itraconazole was administered intravenously to anesthetized dogs, a dose-related negative inotropi effect was documented. In a healthy volunteer study of Itraconazole Injection (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 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 than among those receiving lower total daily doses. This suggests that the risk of heart failure might increase with the total daily dose of itraconazole.

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 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, PRECAUTIONS: Drug Interactions, and ADVERSE REACTIONS: Post-marketing Experience for more information.)

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 Special Populations).

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.

PRECAUTIONS

Hepatotoxicity: Rare cases of serious hepatotoxicity have been observed with itraconazole treatment, including some cases within the first week. In patients with elevated or abnormal liver enzymes or active liver disease, or who have experienced liver toxicity with other drugs, treatment with itraconazole is strongly discouraged unless there is a serious or life threatening situation where the expected benefit exceeds the risk. Liver function monitoring should be done in patients with pre-existing hepatic function abnormalities or those who have experienced liver toxicity with other medications and should be considered in all patients receiving itraconazole. Treatment should be stopped immediately and liver function testing should be conducted in patients who develop signs and symptoms suggestive of liver dysfunction.

If neuropathy occurs that may be attributable to itraconazole oral solution, the treatment should be discontinued.

Neuropathy: If neuropathy occurs that may be attributable to itraconazole oral solution, the treatment should be discontinued.

Hearing Loss: Transient or permanent hearing loss has been reported in patients receiving treatment with itraconazole. Several of these reports included concurrent administration of quinidine which is contraindicated (see BOX WARNING: Drug Interactions, CONTRAINDICATIONS: Drug Interactions and PRECAUTIONS: Drug Interactions). The hearing loss usually resolves when treatment is stopped, but can persist in some patients.

Information for Patients:

• Only itraconazole oral solution has been demonstrated effective for oral and/or esophageal candidiasis. Itraconazole oral solution contains the excipient hydroxypropyl-β-cyclodextrin which produced pancreatic adenocarcinomas in a rat carcinogenicity study. These findings were not observed in a similar mouse carcinogenicity study. The clinical relevance of these findings is unknown. (See 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.

8. ADVERSE REACTIONS

Itraconazole has been associated with rare cases of serious hepatotoxicity, including liver failure and death. Some of these cases had neither pre-existing liver disease nor a serious underlying medical condition. If clinical signs or symptoms develop that are consistent with liver disease, treatment should be discontinued and liver function testing performed. The risks and benefits of itraconazole use should be reassessed. (See WARNINGS: Hepatic Effects and PRECAUTIONS: Hepatotoxicity and Information for Patients.)

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 1 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.

Table 1: Summary of Adverse Events Reported by ≥2% of Itraconazole Treated Patients in U.S. Clinical Trials (Total)

* Of the 350 patients, 209 were treated for oropharyngeal candidiasis in controlled studies, 63 were treated for esophageal candidiasis in controlled studies and 78 were treated for oropharyngeal candidiasis in an open study.

† Of the 125 patients, 62 were treated for oropharyngeal candidiasis and 63 were treated for esophageal candidiasis.

‡ All 81 patients were treated for oropharyngeal candidiasis.

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, tremor, and pulmonary infiltration.

Post-marketing Experience

Adverse drug reactions that have been identified during post-approval use of itraconazole (all formulations) are listed in the table below. Because these reactions are reported voluntarily from a population of uncertain size, reliably estimating their frequency or establishing a causal relationship to drug exposure is not always possible.

Table 2: Postmarketing Reports of Adverse Drug Reactions

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 Special Populations, CONTRAINDICATIONS, WARNINGS, and PRECAUTIONS: Drug Interactions for more information.)

9. OVERDOSAGE

Itraconazole is not removed by dialysis. In the event of accidental overdosage, supportive measures, including gastric lavage with sodium bicarbonate, should be employed.

Limited data exist on the outcomes of patients ingesting high doses of itraconazole. In patients taking either 1000 mg of itraconazole oral solution or up to 3000 mg of itraconazole capsules, the adverse event profile was similar to that observed at recommended doses.

10. DRUG INTERACTIONS

Itraconazole and its major metabolite, hydroxyitraconazole, are inhibitors of CYP3A4. Therefore, the following drug interactions may occur (See Table 3 below and the following drug class subheadings that follow):

1. Itraconazole may decrease the elimination of drugs metabolized by CYP3A4, resulting in increased plasma concentrations of these drugs when they are administered with itraconazole. These elevated plasma concentrations may increase or prolong both therapeutic and adverse effects of these drugs. Whenever possible, plasma concentrations of these drugs should be monitored, and dosage adjustments made after concomitant itraconazole therapy is initiated. When appropriate, clinical monitoring for signs or symptoms of increased or prolonged pharmacologic effects is advised. Upon discontinuation, depending on the dose and duration of treatment, itraconazole plasma concentrations decline gradually (especially in patients with hepatic cirrhosis or in those receiving CYP3A4 inhibitors). This is particularly important when initiating therapy with drugs whose metabolism is affected by itraconazole.

2. Inducers of CYP3A4 may decrease the plasma concentrations of itraconazole. Itraconazole may not be effective in patients concomitantly taking itraconazole and one of these drugs. Therefore, administration of these drugs with itraconazole is not recommended.

3. Other inhibitors of CYP3A4 may increase the plasma concentrations of itraconazole. Patients who must take itraconazole concomitantly with one of these drugs should be monitored closely for signs or symptoms of increased or prolonged pharmacologic effects of itraconazole.

Table 3: Selected Drugs that are predicted to alter the plasma concentration of itraconazole or have their plasma concentration altered by itraconazole

Antiarrhythmics: The class IA antiarrhythmic quinidine and class III antiarrhythmic dofetilide are known to prolong the QT interval. Coadministration of quinidine or dofetilide with itraconazole may increase plasma concentrations of quinidine or dofetilide which could result in serious cardiovascular events. Therefore, concomitant administration of itraconazole and quinidine or dofetilide is contraindicated. (See BOX WARNING, CONTRAINDICATIONS, and WARNINGS.)

The class IA antiarrhythmic disopyramide has the potential to increase the QT interval at high plasma concentrations. Caution is advised when itraconazole and disopyramide are administered concomitantly.

Concomitant administration of digoxin and itraconazole has led to increased plasma concentrations of digoxin.

Anticonvulsants: Reduced plasma concentrations of itraconazole were reported when itraconazole was administered concomitantly with phenytoin. Carbamazepine, phenobarbital, and phenytoin are all inducers of CYP3A4. Although interactions with carbamazepine and phenobarbital have not been studied, concomitant administration of itraconazole and these drugs would be expected to result in decreased plasma concentrations of itraconazole. In addition, in vivo studies have demonstrated an increase in plasma carbamazepine concentrations in subjects concomitantly receiving ketoconazole. Although there are no data regarding the effect of itraconazole on carbamazepine metabolism, because of the similarities between ketoconazole and itraconazole, concomitant administration of itraconazole and carbamazepine may inhibit the metabolism of carbamazepine.

Antimycobacterials: Drug interaction studies have demonstrated that plasma concentrations of azole antifungal agents and their metabolites, including itraconazole and hydroxyitraconazole, were significantly decreased when these agents were given concomitantly with rifabutin or rifampin. In vivo data suggest that rifabutin is metabolized in part by CYP3A4. Itraconazole may inhibit the metabolism of rifabutin. Although no formal study data are available for isoniazid, similar effects should be anticipated. Therefore, the efficacy of itraconazole could be substantially reduced if given concomitantly with one of these agents. Coadministration is not recommended.

Antineoplastics: Itraconazole may inhibit the metabolism of busulfan, docetaxel, and vinca alkaloids. Antipsychotics: Pimozide is known to prolong the QT interval and is partially metabolized by CYP3A4. Coadministration of pimozide with itraconazole could result in serious cardiovascular events. Therefore, concomitant administration of itraconazole and pimozide is contraindicated. (See BOX WARNING, CONTRAINDICATIONS, and WARNINGS.)

Benzodiazepines: Concomitant administration of itraconazole and alprazolam, diazepam, oral midazolam, or triazolam could lead to increased plasma concentrations of these benzodiazepines. Increased plasma concentrations could potentiate and prolong hypnotic and sedative effects. Concomitant administration of itraconazole and oral midazolam or triazolam is contraindicated. (See CONTRAINDICATIONS and WARNINGS.) If midazolam is administered parenterally, special precaution and patient monitoring is required since the sedative effect may be prolonged.

Calcium Channel Blockers: Edema has been reported in patients concomitantly receiving itraconazole and dihydropyridine calcium channel blockers. Appropriate dosage adjustment may be necessary.

Calcium channel blockers can have a negative inotropic effect which may be additive to those of itraconazole; itraconazole can inhibit the metabolism of calcium channel blockers such as dihydropyridines (e.g., nifedipine and felodipine) and verapamil. Therefore, caution should be used when co-administering itraconazole and calcium channel blockers due to an increased risk of CHF. Concomitant administration of itraconazole and nisoldipine is contraindicated. (See WARNINGS, and ADVERSE REACTIONS: Post-marketing Experience for more information).

Gastric Acid Suppressors/Neutralizers: Reduced plasma concentrations of itraconazole were reported when itraconazole capsules were administered concomitantly with H2-receptor antagonists. Studies have shown that absorption of itraconazole is impaired when gastric acid production is decreased. Therefore, itraconazole should be administered with a cola beverage if the patient has achlorhydria or is taking H2-receptor antagonists or other gastric acid suppressors. Antacids should be administered at least 1 hour before or 2 hours after administration of itraconazole capsules. In a clinical study, when itraconazole capsules were administered with omeprazole (a proton pump inhibitor), the bioavailability of itraconazole was significantly reduced.

Gastrointestinal Motility Agents: Coadministration of itraconazole with cisapride can elevate plasma cisapride concentrations which could result in serious cardiovascular events. Therefore, concomitant administration of itraconazole with cisapride is contraindicated. (See BOX WARNING, CONTRAINDICATIONS, and WARNINGS.)

HMG CoA-Reductase Inhibitors: Human pharmacokinetic data suggest that itraconazole inhibits the metabolism of atorvastatin, cerivastatin, lovastatin, and simvastatin, which may increase the risk of skeletal muscle toxicity, including rhabdomyolysis. Concomitant administration of itraconazole with HMG CoAreductase inhibitors, such as lovastatin and simvastatin, is contraindicated. (See CONTRAINDICATIONS and WARNINGS.)

Immunosuppressants: Concomitant administration of itraconazole and cyclosporine or tacrolimus has led to increased plasma concentrations of these immunosuppressants. Concomitant administration of itraconazole and sirolimus could increase plasma concentrations of sirolimus.

Macrolide Antibiotics: Erythromycin and clarithromycin are known inhibitors of CYP3A4 (See Table 2) and may increase plasma concentrations of itraconazole. In a small pharmacokinetic study involving HIV infected patients, clarithromycin was shown to increase plasma concentrations of itraconazole. Similarly, following administration of 1 gram of erythromycin ethyl succinate and 200 mg itraconazole as single doses, the mean Cmax and AUC0-∞ of itraconazole increased by 44% (90% CI: 119-175%) and 36% (90% CI: 108-171%), respectively.

Non-nucleoside Reverse Transcriptase Inhibitors: Nevirapine is an inducer of CYP3A4. In vivo studies have shown that nevirapine induces the metabolism of ketoconazole, significantly reducing the bioavailability of ketoconazole. Studies involving nevirapine and itraconazole have not been conducted. However, because of the similarities between ketoconazole and itraconazole, concomitant administration of itraconazole and nevirapine is not recommended.

In a clinical study, when 8 HIV-infected subjects were treated concomitantly with itraconazole capsules 100 mg twice daily and the nucleoside reverse transcriptase inhibitor zidovudine 8 ± 0.4 mg/kg/day, the pharmacokinetics of zidovudine were not affected. Other nucleoside reverse transcriptase inhibitors have not been studied.

Oral Hypoglycemic Agents: Severe hypoglycemia has been reported in patients concomitantly receiving azole antifungal agents and oral hypoglycemic agents. Blood glucose concentrations should be carefully monitored when itraconazole and oral hypoglycemic agents are coadministered.

Polyenes: Prior treatment with itraconazole, like other azoles, may reduce or inhibit the activity of polyenes such as amphotericin B. However, the clinical significance of this drug effect has not been clearly defined.

Protease Inhibitors: Concomitant administration of itraconazole and protease inhibitors metabolized by CYP3A4, such as indinavir, ritonavir, and saquinavir, may increase plasma concentrations of these protease inhibitors. In addition, concomitant administration of itraconazole and indinavir and ritonavir (but not saquinavir) may increase plasma concentrations of itraconazole. Caution is advised when itraconazole and protease inhibitors must be given concomitantly.

Other:

• Levacetylmethadol (levomethadyl) is known to prolong the QT interval and is metabolized by CYP3A4. Co-administration of levacetylmethadol with itraconazole could result in serious cardiovascular events. Therefore, concomitant administration of itraconazole and levacetylmethadol is contraindicated.

• Elevated concentrations of ergot alkaloids can cause ergotism, ie. a risk for vasospasm potentially leading to cerebral ischemia and/or ischemia of the extremities. Concomitant administration of ergot alkaloids such as dihydroergotamine, ergometrine (ergonovine), ergotamine and methylergometrine (methylergonovine) with itraconazole is contraindicated.

• Halofantrine has the potential to prolong the QT interval at high plasma concentrations. Caution is advised when itraconazole and halofantrine are administered concomitantly.

In vitro data suggest that alfentanil is metabolized by CYP3A4. Administration with itraconazole may increase plasma concentrations of alfentanil.

• Human pharmacokinetic data suggest that concomitant administration of itraconazole and buspirone results in significant increases in plasma concentrations of buspirone.

• Itraconazole may inhibit the metabolism of certain glucocorticosteroids such as budesonide, dexamethasone and methylprednisolone.

In vitro data suggest that trimetrexate is extensively metabolized by CYP3A4. In vitro animal models have demonstrated that ketoconazole potently inhibits the metabolism of trimetrexate. Although there are no data regarding the effect of itraconazole on trimetrexate metabolism, because of the similarities between ketoconazole and itraconazole, concomitant administration of itraconazole and trimetrexate may inhibit the metabolism of trimetrexate.

• Itraconazole enhances the anticoagulant effect of coumarin-like drugs, such as warfarin.

• Cilostazol and eletriptan are CYP3A4 metabolized drugs that should be used with caution when coadministered with itraconazole.

• Fentanyl plasma concentrations could be increased or prolonged by concomitant use of itraconazole and may cause potentially fatal respiratory depression.
11. PHARMACOKINETICS

The absolute bioavailability of itraconazole administered as a non-marketed solution formulation under fed conditions was 55% in 6 healthy male volunteers. However, the bioavailability of itraconazole oral solution is increased under fasted conditions reaching higher maximum plasma concentrations (Cmax) in a shorter period of time. In 27 healthy male volunteers, the steady-state area under the plasma concentration versus time curve (AUC0-24h) of itraconazole (itraconazole oral solution, 200 mg daily for 15 days) under fasted conditions was 131 ± 30% of that obtained under fed conditions. Therefore, unlike itraconazole capsules, it is recommended that itraconazole oral solution be administered without food. Presented in the table below are the steady-state (Day 15) pharmacokinetic parameters for itraconazole and hydroxyitraconazole (itraconazole oral solution) under fasted and fed conditions:

The bioavailability of itraconazole oral solution relative to itraconazole capsules was studied in 30 healthy male volunteers who received 200 mg of itraconazole as the oral solution and capsules under fed conditions. The AUC0-∞ from itraconazole oral solution was 149 ± 68% of that obtained from itraconazole capsules; a similar increase was observed for hydroxyitraconazole. In addition, a cross study comparison of itraconazole and hydroxyitraconazole pharmacokinetics following the administration of single 200 mg doses of itraconazole oral solution (under fasted conditions) or itraconazole capsules (under fed conditions) indicates that when these two formulations are administered under conditions which optimize their systemic absorption, the bioavailability of the solution relative to capsules is expected to be increased further. Therefore, it is recommended that itraconazole oral solution and itraconazole capsules not be used interchangeably. The following table contains pharmacokinetic parameters for itraconazole and hydroxyitraconazole following single 200 mg doses of itraconazole oral solution (n=27) or itraconazole capsules (n=30) administered to healthy male volunteers under fasted and fed conditions, respectively:

The plasma protein binding of itraconazole is 99.8% and that of hydroxyitraconazole is 99.5%. Following intravenous administration, the volume of distribution of itraconazole averaged 796 ± 185 L.

Itraconazole is metabolized predominately by the cytochrome P450 3A4 isoenzyme system (CYP3A4), resulting in the formation of several metabolites, including hydroxyitraconazole, the major metabolite. Results of a pharmacokinetics study suggest that itraconazole may undergo saturable metabolism with multiple dosing. Fecal excretion of the parent drug varies between 3-18% of the dose. Renal excretion of the parent drug is less than 0.03% of the dose. About 40% of the dose is excreted as inactive metabolites in the urine. No single excreted metabolite represents more than 5% of a dose. Itraconazole total plasma clearance averaged 381 ± 95 mL/minute following intravenous administration. (See CONTRAINDICATIONS and PRECAUTIONS: Drug Interactions for more information.)

Special Populations:

Pediatrics: The pharmacokinetics of itraconazole oral solution were studied in 26 pediatric patients requiring systemic antifungal therapy. Patients were stratified by age: 6 months to 2 years (n=8), 2 to 5 years (n=7) and 5 to 12 years (n=11), and received itraconazole oral solution 5 mg/kg once daily for 14 days. Pharmacokinetic parameters at steady-state (Day 14) were not significantly different among the age strata.

Renal Insufficiency: 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. x 1.73 m2, the bioavailability was slightly reduced compared with normal population parameters. This study did not demonstrate any significant effect of hemodialysis or continuous ambulatory peritoneal dialysis on the pharmacokinetics of itraconazole (Tmax, Cmax, and AUC0-8). Plasma concentration-versus-time profiles showed wide intersubject variation in all three groups.

Hepatic Insufficiency: Patients with impaired hepatic function should be carefully monitored when taking itraconazole. The prolonged elimination half-life of itraconazole observed in cirrhotic patients should be considered when deciding to initiate therapy with other medications metabolized by CYP3A4. (See BOX WARNING, CONTRAINDICATIONS, and PRECAUTIONS: Drug Interactions.)

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 Injection (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 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 twice daily for 14 days in a pharmacokinetic study. Sixteen patients completed the study. Steady state trough concentrations >250ng/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 itraconazole oral solution, consideration should be given to switching to alternative therapy.

12. HOW SUPPLIED/STORAGE AND HANDLING

1) How Available:

a) Brand name: SPORANOX Oral Solution, by JANSSEN PHARMACEUTICA N.V.

b) Generic drugs: None.

2) How Supplied:

SPORANOX® (itraconazole) Oral Solution is available in 150 mL amber glass bottles

(NDC 50458-295-15) containing 10 mg of itraconazole per mL.

3) Storage: Store at or below 25°C (77°F). Do not freeze. Keep out of reach of children.

Rx only

Rev 11/11