Itraconazole

Trade Names:
Sporanox
- Capsules 100 mg
- Solution, oral 10 mg/mL

Pharmacology

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Inhibits the CYP-450–dependent synthesis of ergosterol, which is a vital component of fungal cell membranes.

Pharmacokinetics

Absorption

Absolute bioavailability 55%. The mean C _max at steady state is approximately 2,282 ng/mL (capsules) and 1,963 ng/mL (oral solution). The mean T _max at steady state is approximately 4.6 h (capsules) and 2.5 h (oral solution).

Distribution

99.8% of itraconazole and 99.5% of hydroxyitraconazole are protein bound.

Metabolism

The active metabolite is hydroxyitraconazole. Metabolized predominantly by CYP-450 3A4 isoenzyme, resulting in several metabolites.

Elimination

The mean t _½ at steady state is approximately 64 h (capsules) and 39.7 h (oral solution). Approximately 40% is excreted in the urine as inactive metabolites, and 3% to 18% is excreted in the feces as the parent drug.

Special Populations

Bioavailability is slightly reduced.

Prolonged t _½ . Monitor closely. Reduced C _max 147% (capsules).

Indications and Usage

Treatment of aspergillosis, blastomycosis, histoplasmosis, and onychomycosis (non-immunocompromised patients only).

Treatment of oropharyngeal or esophageal candidiasis and empiric treatment of febrile neutropenic patients with suspected fungal infections.

Unlabeled Uses

Recommended as an alternative to fluconazole as secondary prevention of oropharyngeal, vaginal, or esophageal candidiasis in HIV-infected patients who have severe or frequent recurrences.

Alternative to fluconazole for prevention of Cryptococcus in adults with advanced HIV disease (CD4 counts less than 50 cell/mcL) and recommended as an alternative to fluconazole for lifelong secondary prevention of cryptococcal disease in HIV-infected adults; first-line agent in the primary prevention of histoplasmosis in adults with advanced HIV disease (CD4 counts less than 100 cells/mcL) and live in endemic areas (rate of at least 10 cases per 100 patient-years) and also as first-line agent for lifelong secondary prophylaxis; recommended as an alternate agent to fluconazole for lifelong secondary prevention of coccidioidomycosis in HIV-infected adults. Oral itraconazole is recommended also for secondary prevention of histoplasmosis, cryptococcal disease, and coccidioidomycosis in children with HIV; primary prevention of histoplasmosis (first-line agent) and cryptococcal disease (alternate therapy) in children with HIV, with severe immunosuppression, and who live in endemic areas (histoplasmosis).

Contraindications

Coadministration with cisapride, dofetilide, ergot derivatives (eg, ergotamine), nisoldipine, pimozide, quinidine, triazolam, levacetylmethadol (levomethadyl), oral midazolam, or HMG-CoA reductase inhibitors metabolized by the CYP-450 3A enzyme system (eg, lovastatin, simvastatin); not for treatment of onychomycosis in pregnant women or women contemplating pregnancy; ventricular dysfunction such as CHF or history of CHF; hypersensitivity to any component of the product.

Dosage and Administration

PO 200 to 400 mg/day. Give doses higher than 200 mg in 2 divided doses. An inadequate treatment period may lead to recurrence.

PO 100 mg/day (10 mL) for a minimum of 3 wk. Continue treatment for 2 wk following resolution of symptoms. Doses up to 200 mg/day may be used based on medical judgment of the patient's response. Vigorously swish solution in mouth (10 mL at a time) for several seconds and swallow.

PO

Loading dose of 200 mg 3 times daily for 3 days. Continue treatment for a minimum of 3 mo and until clinical parameters and laboratory tests indicate the active fungal infection has subsided.

PO 2 treatment pulses separated by a 3-wk period without itraconazole. Each pulse consisting of 200 mg twice daily for 1 wk.

PO 200 mg/day for 12 wk.

PO 200 mg (20 mL)/day of oral solution for 1 to 2 wk. Vigorously swish solution in mouth (10 mL at a time) for several seconds and swallow. For patients with oropharyngeal candidiasis unresponsive/refractory to treatment with fluconazole tablets, the recommended dose is 100 mg (10 mL) twice daily.

General Advice

• Oral solution and capsules are not interchangeable.

• Administer capsules immediately after a full meal to ensure max absorption.
• Administer capsules with 8 oz of a cola beverage in HIV-infected patient or patient taking gastric acid suppressive therapy (eg, H ₂ -receptor antagonist, proton pump inhibitor) or if the patient has achlorhydria.
• Administer antacids at least 1 h before or 2 h after administration of itraconazole capsules.

• Administer prescribed dose on an empty stomach to ensure max absorption.
• If treating oral or esophageal candidiasis, have patient vigorously swish the solution in mouth for several seconds and swallow.
• Measure prescribed dose using dosing cup, spoon, or syringe.

Storage/Stability

Store capsules at controlled room temperature (59° to 77°F). Protect from light and moisture.

Store oral solution below 77°F. Protect from freezing.

Drug Interactions

Levels may be elevated by itraconazole, increasing the risk of adverse reactions.

Plasma levels of itraconazole may be decreased.

Edema has occurred with concomitant dihydropyridine calcium blockers.

Serious CV events may occur. Coadministration is contraindicated.

The metabolism of these corticosteroids may be inhibited, resulting in increased toxicity.

May decrease therapeutic effects of itraconazole. Administer itraconazole 2 h or more before didanosine.

Coadministration may increase risk of rhabdomyolysis. Lovastatin and simvastatin coadministration is contraindicated.

Hypoglycemia may occur. Monitor blood glucose.

Plasma levels of itraconazole may be increased.

Reduced plasma levels of itraconazole may occur. Avoid use if possible.

Levels may be elevated by itraconazole, increasing the risk of adverse reactions. Avoid use if possible.

Laboratory Test Interactions

None well documented.

Adverse Reactions

The incidence and type of adverse reaction vary depending on usage and route of administration.

Cardiovascular

Hypertension (3%); hypotension, orthostatic hypotension, tachycardia, vasculitis (1%); CHF (postmarketing).

CNS

Headache (4%); fatigue (3%); depression, dizziness (2%); decreased libido, malaise, somnolence, vertigo (1%); hypoesthesia, paresthesia, peripheral neuropathy (postmarketing).

Dermatologic

Rash (9%); increased sweating (4%); pruritus (3%); skin disorder (2%); hypotension (1%); alopecia, erythema multiforme, exfoliative dermatitis, leukocytoclastic vasculitis, photosensitivity, Stevens-Johnson syndrome, toxic epidermal necrolysis, urticaria (postmarketing).

EENT

Ophthalmic malformations, tinnitus, visual disturbances including blurred vision and diplopia (postmarketing).

GI

Diarrhea, nausea (11%); vomiting (7%); abdominal pain (6%); GI disorders (4%); constipation (2%); anorexia (1%); dysgeusia, dyspepsia (postmarketing).

Genitourinary

Abnormal renal function, albuminuria, impotence (1%); erectile dysfunction, menstrual disorder, pollakiuria, urinary incontinence (postmarketing).

Hematologic-Lymphatic

Leukopenia, neutropenia, thrombocytopenia (postmarketing).

Hepatic

Bilirubinemia (6%); elevated liver enzymes (4%); abnormal hepatic function, ALT increased (3%); AST increased, jaundice (2%); hepatitis, hepatotoxicity (some fatal), reversible increases in hepatic enzymes (postmarketing).

Metabolic-Nutritional

Hypokalemia (9%); hypertriglyceridemia, increased serum creatinine (3%); hypomagnesemia, increased alkaline phosphatase, increased LDH (2%); fluid overload, hypocalcemia, increased BUN (1%).

Musculoskeletal

Myalgia, rigors (1%); arthralgia (postmarketing).

Respiratory

Coughing (4%); increased sputum, dyspnea, pneumonia, sinusitis (2%); pulmonary edema (postmarketing).

Miscellaneous

Fever (7%); edema (4%); chest pain (3%); pain, Pneumocystis carinii infection (2%); anaphylactic, anaphylactoid, and allergic reactions, anaphylaxis, angioneurotic edema, chromosomal and multiple malformations, peripheral edema, serum sickness (postmarketing).

Precautions

Pregnancy

Category C .

Lactation

Excreted in breast milk.

Children

Safety and efficacy not established.

Elderly

Use with caution because of the greater frequency of decreased hepatic, renal, or cardiac function, and concomitant diseases or other drug therapy.

Renal Function

Use with caution because of limited available data.

Hepatic Function

Rare cases of serious hepatotoxicity, including liver failure and death, have been reported.

HIV-infected patients

Absorption may be decreased in HIV-infected patients with hypochlorhydria.

Overdosage

Symptoms

Limited data available.

Patient Information

• Advise patient to read patient information leaflet before starting therapy and with each refill.
• Review dosing schedule and prescribed length of therapy with patient. Advise patient that treatment may be prolonged (eg, several weeks or months) and to continue medication until advised to stop using by health care provider.

• Capsules and Oral Solution
• Caution patient that capsules and oral solution cannot be used interchangeably.
• Advise patient to take capsules after a full meal to obtain max benefit.
• Advise HIV-infected patient or patient receiving gastric acid suppressive therapy (eg, H ₂ -receptor antagonist, proton pump inhibitor) to take capsules with 8 oz of a cola beverage to obtain max benefit.
• Advise patient using antacids to take the antacid at least 1 h before or 2 h after taking itraconazole capsules.
• Advise patient using oral solution to measure prescribed dose with dosing cup, spoon, or syringe and to take prescribed dose on an empty stomach to obtain max benefit.
• Advise patient using oral solution to treat oral or esophageal candidiasis to vigorously swish the solution in mouth for several seconds and then swallow.
• Advise patient that if a dose is missed, to take as soon as remembered. However, if it is nearing the time for the next dose, advise patient to skip the dose and take the next dose at the regularly scheduled time.
• Remind patient to complete entire course of therapy, even if symptoms of infection have disappeared.
• Advise patient to inform health care provider if infection does not improve or worsens.
• Advise patient to contact health care provider immediately if any of the following occur: swelling of feet, ankles, or legs; difficulty breathing or unexplained shortness of breath; skin rash; fatigue; numbness or tingling in hands and/or feet; persistent appetite loss, nausea, or vomiting; dark urine; pale stools; yellowing of skin or eyes.
• Advise women of childbearing potential being treated for onychomycosis to use effective contraceptive measures during treatment and for 2 mo following discontinuation of therapy.

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