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All about: Itraconazole

Big Image Pronouncation: (ih-truh-KAHN-uh-zole)
Class: Triazole antifungal

Trade Names:
Sporanox
- Capsules 100 mg
- Oral Solution 10 mg/mL
- Injection 10 mg/mL

Mechanism of Action

Pharmacology

Inhibits the C-demethylation step in the synthesis of ergosterol, which is a vital component of fungal cell membranes.

Pharmacokinetics

Absorption

The mean C max at steady state is approximately 2,856 ng/mL (IV) and 2,010 ng/mL (oral). The mean C max at steady state (active metabolites) is approximately 1,906 ng/mL (IV) and 2614 ng/mL (oral). The mean T max at steady state is approximately 1.08 h (IV) and approximately 4 h (oral). The mean T max at steady state (active metabolites) is approximately 8.53 h (IV) and approximately 6 h (oral).

Distribution

99.8% (itraconazole) and 99.5% (hydroxyitraconazole) are protein bound. The Vd is approximately 796 L (IV).

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 35 h. Approximately 40% is excreted in the urine as inactive metabolites, and 3% to 18% is excreted in the feces as the parent drug. The Cl is approximately 381 mL/min (IV).

Special Populations

Renal Function Impairment

If the CrCl is less than 19 mL/min, the Cl decreases 6-fold. Itraconazole injection should not be used with CrCl less than 30 mL/min (IV).

Hepatic Function Impairment

Prolonged t ½ . Monitor closely. Reduced C max 147% (oral).

Indications and Usage

Injection

Treatment of aspergillosis, blastomycosis, histoplasmosis, and the empiric treatment of febrile neutropenic patients with suspected fungal infections.

Capsules

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

Oral solution

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

Unlabeled Uses

Treatment of superficial mycoses (eg, dermatophytoses); systemic mycoses (eg, cryptococcus, coccidioidomycosis).

Contraindications

Coadministration with cisapride, dofetilide, ergot derivatives (eg, ergotamine), pimozide, quinidine, triazolam, levacetylmethadol (levomethadyl), oral midazolam, 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.

Dosage and Administration

Aspergillosis, Blastomycosis, Histoplasmosis
Adults

PO 200 to 400 mg/day. Give doses over 200 mg in 2 divided doses. IV 200 mg twice daily for 4 doses, followed by 200 mg/day. Infuse over 1 h. Continue IV for 14 days followed by PO for 3 mo or more and until clinical parameters and laboratory tests indicate active fungal infection has subsided. An inadequate treatment period may lead to recurrence.

Empiric Therapy in Febrile, Neutropenic Patients with Suspected Fungal Infections
Adults

IV 200 mg twice daily infused over 60 min for 4 doses, followed by 200 mg once daily for up to 14 days; continue PO oral solution 200 mg twice daily until resolution of clinically important neutropenia (safety and efficacy over 28 days not established.)

Esophageal Candidiasis
Adults

PO 100 mg/day 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.

Onychomycosis, Fingernails Only
Adults

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

Onychomycosis, Toenails With or Without Fingernail Involvement
Adults

PO 200 mg/day for 12 wk.

Oropharyngeal Candidiasis
Adults

PO , oral solution 200 mg (20 mL)/day for 1 to 2 wk. Vigorously swish solution in mouth for several seconds and swallow.

General Advice

  • Oral solution and capsules are not interchangeable.
  • No dosage adjustment is necessary when switching from IV to oral therapy.
Capsules
  • 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).
  • Administer antacids at least 1 h before or 2 h after administration of itraconazole capsules.
Oral solution
  • 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.
Injection
  • For IV infusion only. Not for intradermal, intrathecal, intraperitoneal, subcutaneous, IM, or IV bolus administration.
  • Use only the components included in the injection kit. Do not substitute. Follow manufacturer's instructions for reconstituting and administering injectable itraconazole using kit components.
  • Do not mix with any other diluent than sodium chloride 0.9% injection.
  • Do not administer if solution is cloudy, discolored, or contains particulate matter.
  • Do not add other medications or additives to injection bag or through same line used for itraconazole.
  • Administer prescribed dose through dedicated infusion line over 60 min using filtered infusion set provided. Flush infusion set with 15 to 20 mL sodium chloride 0.9% injection over 30 sec to 15 minutes. Do not use bacteriostatic sodium chloride injection. Discard the entire infusion line after flushing with sodium chloride.

Storage/Stability

Capsules

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

Oral solution

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

Injection

Store infusion kit below 77°F. Protect from light and freezing. After reconstitution, store diluted itraconazole injection in refrigerator (36° to 46°F) or at controlled room temperature (59° to 77°F) for up to 48 h if protected from light. Exposure to normal room light is acceptable during administration.

Drug Interactions

Alfentanil, almotriptan, alprazolam, aripiprazole, atorvastatin, buspirone, busulfan, carbamazepine, cerivastatin, cilostazol, cyclophosphamide, cyclosporine, diazepam, digoxin, disopyramide, docetaxel, eletriptan, halofantrine, haloperidol, protease inhibitors, sildenafil, sirolimus, tacrolimus, tadalafil, tolterodine, trimetrexate, vardenafil, warfarin, zolpidem

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

Antacids, carbamazepine, isoniazid, phenobarbital, proton pump inhibitors

Plasma levels of itraconazole may be decreased.

Calcium blockers (eg, amlodipine, felodipine, nifedipine, verapamil)

Edema has occurred with concomitant dihydropyridine calcium blockers.

Cisapride, dofetilide, eplerenone, ergot alkaloids, levacetylmethadol, lovastatin, oral midazolam, pimozide, quinidine, simvastatin, triazolam

Serious CV events may occur. Coadministration is contraindicated.

Corticosteroids (eg, budesonide, dexamethasone, methylprednisolone)

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

Didanosine (buffered)

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

Hypoglycemic agents

Hypoglycemia may occur. Monitor blood glucose.

Macrolide antibiotics (eg, clarithromycin, erythromycin), protease inhibitors (eg, indinavir, ritonavir)

Plasma levels of itraconazole may be increased.

Nevirapine, phenytoin, rifamycins

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

Phenytoin, rifamycins, vinca alkaloids

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

Laboratory Test Interactions

None well documented.

Adverse Reactions

Incidence and type of reactions vary depending on usage and route of administration. In general, the adverse reactions listed occur in at least 1% of the patients treated.

Cardiovascular

Hypertension; hypotension; orthostatic hypotension; tachycardia; vasculitis; CHF (postmarketing).

CNS

Abnormal dreaming; anxiety; decreased libido; depression; dizziness; headache; insomnia; somnolence; vertigo; peripheral neuropathy (postmarketing).

Dermatologic

Increased sweating; pruritus; rash; alopecia, photosensitivity, Stevens-Johnson syndrome (postmarketing).

GI

Abdominal pain; anorexia; constipation; diarrhea; dyspepsia; flatulence; gastritis; gastroenteritis; general GI disorders; gingivitis; increased appetite; nausea; ulcerative stomatitis; vomiting.

Genitourinary

Abnormal renal function; albuminuria; cystitis; impotence; menstrual disorders.

Hematologic

Neutropenia (postmarketing).

Hepatic

Abnormal liver function; ALT increased; AST increased; bilirubinemia; elevated liver enzyme; jaundice; hepatitis, liver failure, reversible increases in hepatic enzymes (postmarketing).

Metabolic

Alkaline phosphatase increased; BUN increased; fluid overload; hypocalcemia; hypokalemia; hypomagnesemia; hypophosphatemia; LDH increased; serum creatinine increased; hypertriglyceridemia (postmarketing).

Respiratory

Coughing; dyspnea; pharyngitis; pneumonia; rhinitis; pulmonary infiltration; sinusitis; sputum increased; upper respiratory tract infection.

Miscellaneous

Application site reaction; asthenia; back pain; bursitis; chest pain; edema; fatigue; fever; gamma-GT increased; herpes zoster; hypertriglyceridemia; injury; malaise; myalgia; pain; Pneumocystis carinii infection; rigors; tremor; vein disorder; anaphylactic and allergic reactions, peripheral edema (postmarketing).

Precautions

Warnings

Not to be administered for treatment of onychomycosis patients with evidence of ventricular dysfunction (eg, CHF) or history of CHF. Monitor for signs and symptoms of CHF; discontinue if they develop. Coadministration of cisapride, levacetylmethadol (levomethadyl), dofetilide, pimozide, or quinidine is contraindicated. Serious CV events, including arrhythmias and QT prolongation, may occur.


Monitor

Hepatic injury

Monitor patient for signs and symptoms of hepatic injury (fatigue, right upper quadrant abdominal pain, persistent appetite loss or nausea, vomiting, dark urine, yellowing of skin or eyes).


Pregnancy

Category C .

Lactation

Excreted in breast milk. Weigh benefits to mother against potential risk to infant.

Children

Safety and efficacy not established. Patients 6 mo to 16 yr of age have been treated with no serious adverse reactions reported; however, the long-term effect in children is unknown.

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

Do not use injection in patients with severe renal function impairment (CrCl less than 30 mL/min). Ensure that renal function and liver enzymes are determined before starting therapy and periodically during prolonged treatment (longer than 1 mo).

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 individuals with hypochlorhydria.

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 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.
  • Injection
  • Advise patient that medication will be prepared and administered by a health care professional in a health care setting when oral therapy is not feasible but that the patient will be switched to oral therapy when health care provider believes it is appropriate.

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