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Itraconazole

Pronunciation

Pronunciation: IT-ra-KON-a-zole
Class: Triazole antifungal

Trade Names

Sporanox
- Capsules, oral 100 mg
- Solution, oral 10 mg/mL

Pharmacology

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

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Pharmacokinetics

Absorption

Absolute bioavailability is 55%. The mean C max at steady state is approximately 2,282 ng/mL (capsules with food), 1,435 ng/mL (oral solution with food), and 1,963 ng/mL (oral solution without food). 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. Vd is 796 L.

Metabolism

The major metabolite is hydroxyitraconazole. Metabolized predominantly by CYP3A4 isoenzyme, resulting in several metabolites.

Elimination

The mean half-life at steady state is approximately 64 h (capsules), 37.4 h (oral solution without food), and 39.7 h (oral solution without food). 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

Renal Function Impairment

Bioavailability is slightly reduced.

Hepatic Function Impairment

C max was reduced by 47% and resulted in a 2-fold increase in half-life (capsules).

Children

C max is about 582.5 ng/mL and half-life is about 35.8 h.

Cystic fibrosis

Large variabilities in pharmacokinetics of oral solution are observed in patients with cystic fibrosis.

Indications and Usage

Capsules

Treatment of aspergillosis, blastomycosis, and histoplasmosis in immunocompromised and nonimmunocompromised patients; treatment of onychomycosis of fingernail or toenail, with or without fingernail involvement, in nonimmunocompromised patients.

Solution

Treatment of oropharyngeal or esophageal candidiasis.

Unlabeled Uses

Infection prophylaxis in neutropenic adults.

Capsules

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

Solution

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.

Contraindications

Coadministration with cisapride, dofetilide, ergot derivatives (eg, dihydroergotamine, ergonovine, ergotamine, methylergonovine), felodipine, nisoldipine, methadone, pimozide, quinidine, triazolam, levacetylmethadol (levomethadyl), oral midazolam, or HMG-CoA reductase inhibitors metabolized by the CYP3A enzyme system (eg, lovastatin, simvastatin); for treatment of onychomycosis in pregnant women or women contemplating pregnancy (capsules); for treatment of onychomycosis in patients with ventricular dysfunction, such as CHF or history of CHF (capsules), or patients with evidence of ventricular dysfunction, such as CHF or a history of CHF, except for the treatment of life-threatening or other serious infections (oral solution); hypersensitivity to any component of the product.

Dosage and Administration

Aspergillosis
Adults

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

Blastomycosis, Histoplasmosis
Adults

PO 200 mg/day is the usual dose. If there is no obvious improvement, or if there is evidence of progressive fungal disease, increase the dose in 100 mg increments (max, 400 mg/day).

Esophageal Candidiasis
Adults

PO 100 mg/day (10 mL) for a minimum of 3 wk. Continue treatment for 2 wk following resolution of symptoms. Dosages of up to 200 mg/day may be used based on medical judgment of the patient's response.

Life-Threatening Situations
Adults Capsules

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.

Onychomycosis of the Fingernails
Adults

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

Onychomycosis of the Toenails
Adults

PO 200 mg/day for 12 wk.

Oropharyngeal Candidiasis
Adults

PO 200 mg (20 mL) per day of oral solution for 1 to 2 wk. For patients with oropharyngeal candidiasis unresponsive/refractory to treatment with fluconazole tablets, the recommended dosage is 100 mg (10 mL) twice daily.

General Advice

  • Oral solution and capsules are not interchangeable.
  • Administer capsules with or after a full meal. Oral solution should be taken without food, if possible.
  • Solution should be swished vigorously in the mouth (10 mL at a time) for several seconds, then swallowed.
  • Give dosages above 200 mg/day in 2 divided doses.
  • Obtain specimens for fungal cultures and other relevant laboratory studies (eg, wet mount, histopathology, serology) before therapy to isolate and identify causative organisms. Therapy may be instituted before the results of the cultures and other laboratory studies are known; however, once these results become available, anti-infective therapy should be adjusted accordingly.

Storage/Stability

Store capsules between 59° and 77°F. Protect from light and moisture. Store oral solution at or below 77°F. Do not freeze.

Drug Interactions

Aliskiren

Pharmacologic and adverse effects of aliskiren may be increased. Avoid coadministration.

Almotriptan, alprazolam, atorvastatin, buspirone, busulfan, carbamazepine, cilostazol, cyclophosphamide, cyclosporine, diazepam, digoxin, disopyramide, halofantrine, haloperidol, protease inhibitors (eg, indinavir, ritonavir), quetiapine, risperidone, salmeterol, sildenafil, sirolimus, tacrolimus, tadalafil, vardenafil, venlafaxine, zolpidem

Levels may be elevated by itraconazole, increasing the risk of adverse reactions. Use with caution. Closely monitor the clinical response to these agents when itraconazole is started or stopped. Monitor plasma concentrations of these agents when appropriate. Adjust the dose as needed.

Alpha-1 adrenergic blockers (eg, alfuzosin, silodosin, tamsulosin)

Coadministration of alfuzosin or silodosin with itraconazole is contraindicated. Coadministration of tamsulosin with itraconazole is not recommended.

Amphotericin B

Studies suggest that amphotericin B activity may be suppressed by prior azole antifungal therapy. Clinical importance is unknown.

Antacids, carbamazepine, H 2 -receptor antagonists (eg, cimetidine), isoniazid, orange juice, proton pump inhibitors

Plasma levels of itraconazole may be decreased.

Aripiprazole

Aripiprazole plasma concentrations may be elevated, increasing the pharmacologic and adverse effects. Reduce the aripiprazole dose to 50% of the normal dose when coadministering itraconazole.

Axitinib, cabazitaxel, crizotinib, docetaxel, everolimus, ixabepilone, lurasidone, mefloquine, nilotinib, rivaroxaban, romidepsin, temsirolimus, ticagrelor

Itraconazole may inhibit metabolism of these agents, increasing the pharmacologic effects and risk of adverse reactions. Avoid coadministration.

Bortezomib, eszopiclone, gefitinib, quetiapine, ramelteon, trimetrexate

Itraconazole may inhibit metabolism of these agents, increasing the pharmacologic effects and risk of adverse reactions. Monitor the clinical response and for adverse reactions. A dose reduction for these agents may be needed.

Brentuximab, risperidone, vemurafenib

Itraconazole may inhibit metabolism of these agents, increasing the pharmacologic effects and risk of adverse reactions. If coadministration cannot be avoided, close clinical and laboratory monitoring is warranted.

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

Edema has occurred with concomitant dihydropyridine calcium blockers. Use with caution and adjust the calcium channel blocker dose as needed. Concomitant use of felodipine or nisoldipine with itraconazole is contraindicated.

Cinacalcet

Itraconazole may inhibit cinacalcet metabolism, increasing the pharmacologic effects and risk of adverse reactions. Monitor parathyroid hormone and calcium concentrations when starting or stopping itraconazole. Observe patients for treatment-related adverse reactions. Adjust the dose of cinacalcet as needed.

Cisapride, dofetilide, dronedarone, eplerenone, ergot derivatives (eg, dihydroergotamine, ergonovine, ergotamine, methylergonovine), levomethadyl, lovastatin, nisoldipine, oral midazolam, pimozide, quinidine, ranolazine, simvastatin, triazolam, vasopressin receptor antagonists (eg, conivaptan, tolvaptan)

Serious adverse events may occur. Coadministration is contraindicated.

Colchicine

Colchicine plasma concentrations may be increased. Life-threatening and fatal colchicine toxicity may occur. A colchicine dosing adjustment is required for patients with normal renal or hepatic function receiving itraconazole. Coadministration of itraconazole and colchicine is contraindicated in patients with renal or hepatic impairment.

Contraceptives, hormonal

The efficacy of hormonal contraceptives may be reduced. In addition, elevated ethinyl estradiol blood levels may occur. Inform women of the possible increased risk of hormonal contraceptive failure. Consider an alternative method of contraception. Monitor for increased ethinyl estradiol adverse reactions.

Corticosteroids (eg, budesonide, dexamethasone, fluticasone, methylprednisolone)

The metabolism of these corticosteroids may be inhibited, resulting in increased toxicity. Monitor patients for adverse effects and adjust the corticosteroid dose accordingly.

Didanosine (buffered)

May decrease therapeutic effects of itraconazole. Administer itraconazole at least 2 h before didanosine.

Efavirenz, nevirapine

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

Eletriptan

Plasma concentrations of eletriptan may be elevated, increasing the pharmacologic effects and risk of adverse reactions. Eletriptan should not be taken within 72 h of itraconazole.

Food

The oral bioavailability of itraconazole capsules is maximal when taken with a full meal. The absorption of itraconazole capsules was increased when coadministered with a cola beverage. The bioavailability of itraconazole oral solution is increased under fasted conditions and reaches a higher C max in a shorter period of time. Therefore, unlike itraconazole capsules, it is recommended that itraconazole oral solution be administered without food.

Hepatitis C virus protease inhibitors (eg, boceprevir, telaprevir)

Plasma concentrations and pharmacologic effects of hepatitis C virus (HCV) protease inhibitors and itraconazole may be increased. Close clinical and laboratory monitoring for HCV protease inhibitor–related and itraconazole-related toxicity is warranted. The maximum daily recommended dose of itraconazole is 200 mg in patients receiving HCV protease inhibitors.

Hypoglycemic agents (eg, sulfonylureas)

Hypoglycemia may occur. Monitor blood glucose. Adjust the hypoglycemic dose as needed.

Iloperidone

Itraconazole may inhibit iloperidone metabolism, increasing the pharmacologic effects and risk of adverse reactions. Reduce the iloperidone dose by one-half when coadministered with itraconazole. If therapy with itraconazole is discontinued, the iloperidone dose should be increased to the original dose.

Ivacaftor

Itraconazole may inhibit ivacaftor metabolism, increasing the pharmacologic effects and risk of adverse reactions. The ivacaftor dosage should be reduced to 150 mg twice a week in patients receiving itraconazole.

Macrolide antibiotics (eg, clarithromycin, erythromycin)

Plasma levels of itraconazole may be increased. In addition, macrolide antibiotic concentrations may be elevated. Increased macrolide antibiotic concentrations have been associated with life-threatening cardiac arrhythmias, including torsades de pointes. Avoid coadministration.

Maraviroc

Maraviroc plasma concentrations may be elevated, increasing the risk of adverse reactions. Maraviroc dosage adjustment is recommended. Coadministration is contraindicated in patients with severe renal failure (CrCl 30 mL/min or less).

Methadone

Concomitant use may increase methadone concentrations, resulting in serious cardiac effects. Coadministration is contraindicated.

Mifepristone

Itraconazole may inhibit mifepristone metabolism, increasing the pharmacologic effects and risk of adverse reactions. The mifepristone dosage should not exceed 300 mg daily in patients receiving itraconazole.

Opioid analgesics (eg, alfentanil, buprenorphine, fentanyl, oxycodone)

Pharmacologic and adverse effects of opioid analgesics may be increased. Use with caution. Decrease the opioid analgesic dose as needed.

Phenytoin, rifamycins, vinca alkaloids

Levels may be elevated by itraconazole, increasing the risk of adverse reactions. Avoid concurrent use if possible. May decrease itraconazole levels, resulting in antifungal failure. Increased itraconazole dosage may be needed.

Protease inhibitors (eg, indinavir, ritonavir [but not saquinavir])

Plasma concentrations of itraconazole may be increased.

Ruxolitinib

Itraconazole may inhibit ruxolitinib metabolism, increasing the pharmacologic effects and risk of adverse reactions. A starting dosage of ruxolitinib 10 mg twice daily is recommended in patients with a platelet count of 100 × 10 9 /L or more receiving itraconazole. Further dosage adjustments should be based on clinical and laboratory monitoring.

Saxagliptin

Itraconazole may inhibit saxagliptin metabolism, increasing the pharmacologic effects and risk of adverse reactions. Limit the saxagliptin dosage to 2.5 mg daily in patients receiving itraconazole.

Tolterodine

Tolterodine plasma concentrations may be elevated, increasing the pharmacologic effects and risk of adverse reactions. Patients receiving itraconazole should not receive more than tolterodine 1 mg twice daily.

Toremifene

Toremifene plasma concentrations and pharmacologic effects may be increased. Toxicity, including additive QT prolongation, may occur. Avoid coadministration.

Tyrosine kinase receptor inhibitors (eg, dasatinib, erlotinib, lapatinib, pazopanib, sorafenib, sunitinib)

Tyrosine kinase receptor inhibitor plasma concentrations may be elevated, increasing the pharmacologic effects and risk of adverse reactions. If coadministration of itraconazole cannot be avoided, a tyrosine kinase receptor inhibitor dosage reduction may be needed.

Vilazodone

Itraconazole may inhibit vilazodone metabolism, increasing the pharmacologic effects and risk of adverse reactions. Reduce the dose of vilazodone to 20 mg in patients receiving itraconazole.

Adverse Reactions

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

Cardiovascular

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

CNS

Headache (10%); anxiety, depression, fatigue, malaise (3%); abnormal dreaming, asthenia, dizziness, tremor (2%); insomnia (less than 2%); decreased libido, somnolence, vertigo (1%); hypesthesia, paresthesia, peripheral neuropathy (postmarketing).

Dermatologic

Rash (9%); pruritus (5%); increased sweating (4%); skin disorder (2%); alopecia, erythema multiforme, exfoliative dermatitis, leukocytoclastic vasculitis, photosensitivity, Stevens-Johnson syndrome, TEN, urticaria (postmarketing).

EENT

Gingivitis (3%); pharyngitis (2%); dysphagia, tinnitus, vision abnormal (less than 2%); transient or permanent hearing loss, visual disturbances including blurred vision and diplopia (postmarketing).

GI

Diarrhea, nausea (11%); vomiting (7%); abdominal pain (6%); GI disorders (4%); constipation, ulcerative stomatitis (3%); dyspepsia, flatulence, hemorrhoids, taste perversion (less than 2%); anorexia (1%); dysgeusia, pancreatitis (postmarketing).

Genitourinary

Gynecomastia, hematuria, male breast pain (less than 2%); albuminuria, impotence (1%); erectile dysfunction, menstrual disorder, pollakiuria, urinary incontinence (postmarketing).

Hematologic-Lymphatic

Leukopenia, neutropenia, thrombocytopenia (postmarketing).

Hepatic

Elevated liver enzymes (4%); abnormal hepatic function (3%); hepatotoxicity; liver failure; hepatitis, reversible increases in hepatic enzymes, serious hepatotoxicity (including acute liver failure) (postmarketing).

Hypersensitivity

Anaphylactic/allergic reactions, anaphylaxis, angioneurotic edema (postmarketing).

Metabolic-Nutritional

Edema (4%); hypertriglyceridemia (3%); hypokalemia (2%); adrenal insufficiency, dehydration, weight decrease (less than 2%); pulmonary edema (postmarketing).

Musculoskeletal

Bursitis (3%); back pain, myalgia, rigors (less than 2%); arthralgia (postmarketing).

Respiratory

Coughing (4%); dyspnea, increased sputum (3%); pneumonia, sinusitis (2%); upper respiratory tract infection (less than 2%).

Miscellaneous

Fever (7%); chest pain, pain (3%); Pneumocystis carinii infection (2%); hot flushes, implantation complication, injury, unspecified infection (less than 2%); congenital abnormalities (including chromosomal, skeletal, GU tract, CV, and ophthalmic malformations), peripheral edema, serum sickness (postmarketing).

Precautions

Warnings

Do not administer for the treatment of onychomycosis in patients with evidence of ventricular dysfunction, such as CHF or a history of CHF. If signs or symptoms of CHF occur during administration of itraconazole oral solution, reassess continued itraconazole use. If signs or symptoms of CHF occur during administration of itraconazole capsule, discontinue administration. Coadministration of cisapride, oral midazolam, nisoldipine, felodipine, pimozide, quinidine, dofetilide, triazolam, lovastatin, simvastatin, ergot alkaloids such as dihydroergotamine, ergometrine (ergonovine), ergotamine, and methylergometrine (methylergonovine), methadone, or levacetylmethadol (levomethadyl) with itraconazole is contraindicated. Serious CV events, including QT prolongation, torsades de pointes, ventricular tachycardia, cardiac arrest, and/or sudden death, have occurred in patients using cisapride, pimozide, methadone, levacetylmethadol (levomethadyl), or quinidine concomitantly with itraconazole.


Monitor

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


Pregnancy

Category C . Do not administer itraconazole for the treatment of onychomycosis unless patient uses effective measures to prevent therapy and begins itraconazole on the second or third day following the onset of menses. Effective contraception should be continued throughout therapy and for 2 mo after discontinuation.

Lactation

Excreted in breast milk.

Children

Safety and efficacy not established.

Elderly

Use with caution. Transient or permanent hearing loss has been reported in patients receiving itraconazole.

Hypersensitivity

Use caution when prescribing itraconazole to patients with hypersensitivity to other azoles.

Renal Function

Use with caution because of limited available data.

Hepatic Function

Use with caution because of limited available data.

Cardiac disease

Itraconazole has been associated with reports of CHF. Cases of CHF, peripheral edema, and pulmonary edema have been reported in the postmarketing period among patients being treated for onychomycosis and/or systemic fungal infections.

Cystic fibrosis

Consider switching to alternative therapy if patient is not responding to the oral solution.

Hearing loss

Transient or permanent hearing loss has been reported, sometimes when coadministered with quinidine, which is contraindicated.

Hepatic effects

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

Interchangeability

Do not use itraconazole capsules and itraconazole oral solution interchangeably. This is because drug exposure is greater with the oral solution than with the capsules when the same dose of the drug is given. In addition, the topical effects of mucosal exposure may be different between the 2 formulations.

Neuropathy

Discontinue administration if neuropathy occurs that may be attributable to itraconazole.

Neutropenic patients

Use of oral solution as treatment of oropharyngeal and/or esophageal candidiasis was not investigated in severely neutropenic patients. Not recommended for initiation of treatment in patients at immediate risk of systemic candidiasis.

Overdosage

Symptoms

Limited data available.

Patient Information

  • Inform patients that the topical effects of mucosal exposure may be different between the itraconazole capsules and oral solution. Only the oral solution has been demonstrated to be effective for oral and/or esophageal candidiasis.
  • Advise patients not to use itraconazole capsules interchangeably with itraconazole oral solution.
  • Instruct patients about the signs and symptoms of CHF, and if these signs or symptoms occur during itraconazole administration, to discontinue itraconazole and contact their health care provider immediately.
  • Instruct patients to stop itraconazole treatment immediately and contact their health care provider if any signs and symptoms suggestive of liver dysfunction develop. Such signs and symptoms may include anorexia, dark urine, unusual fatigue, jaundice, nausea and/or vomiting, or pale stools.
  • Instruct patients to contact their health care provider 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 health care provider if any hearing loss symptoms occur.
  • Advise women of childbearing potential being treated for onychomycosis to use effective contraceptive measures during treatment and for 2 mo following discontinuation of therapy.
  • Instruct patients to take itraconazole capsules with a full meal. Instruct patients to take itraconazole oral solution without food, if possible.
  • Advise patients that itraconazole oral solution contains the excipient hydroxypropyl-beta-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.
  • Instruct patients taking itraconazole oral solution for the treatment of oropharyngeal and esophageal candidiasis to vigorously swish in the mouth (10 mL at a time) for several seconds and swallow.

Copyright © 2009 Wolters Kluwer Health.

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